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Wang J, Meng S, Chen Y, Wang H, Hu W, Liu S, Huang L, Xu J, Li Q, Wu X, Huang W, Huang Y. MSC-mediated mitochondrial transfer promotes metabolic reprograming in endothelial cells and vascular regeneration in ARDS. Redox Rep 2025; 30:2474897. [PMID: 40082392 PMCID: PMC11912292 DOI: 10.1080/13510002.2025.2474897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are a potential therapy for acute respiratory distress syndrome (ARDS), but their mechanisms in repairing mitochondrial damage in ARDS endothelial cells remain unclear. METHODS We first examined MSCs' mitochondrial transfer ability and mechanisms to mouse pulmonary microvascular endothelial cells (MPMECs) in ARDS. Then, we investigated how MSC-mediated mitochondrial transfer affects the repair of endothelial damage. Finally, we elucidated the mechanisms by which MSC-mediated mitochondrial transfer promotes vascular regeneration. RESULTS Compared to mitochondrial-damaged MSCs, normal MSCs showed a significantly higher mitochondrial transfer rate to MPMECs, with increases of 41.68% in vitro (P < 0.0001) and 10.50% in vivo (P = 0.0005). Furthermore, MSC-mediated mitochondrial transfer significantly reduced reactive oxygen species (P < 0.05) and promoted proliferation (P < 0.0001) in MPMECs. Finally, MSC-mediated mitochondrial transfer significantly increased the activity of the tricarboxylic acid (TCA) cycle (MD of CS mRNA: 23.76, P = 0.032), and further enhanced fatty acid synthesis (MD of FAS mRNA: 6.67, P = 0.0001), leading to a 6.7-fold increase in vascular endothelial growth factor release from MPMECs and promoted vascular regeneration in ARDS. CONCLUSION MSC-mediated mitochondrial transfer to MPMECs activates the TCA cycle and fatty acid synthesis, promoting endothelial proliferation and pro-angiogenic factor release, thereby enhancing vascular regeneration in ARDS.
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Affiliation(s)
- Jinlong Wang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
- Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China
| | - Shanshan Meng
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Yixuan Chen
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Haofei Wang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Wenhan Hu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Shuai Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Lili Huang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Jingyuan Xu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Qing Li
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Xiaojing Wu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Wei Huang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Yingzi Huang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
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Yang S, Zhu H, Jin H, Wang K, Song J, Sun N, Liu Y, Yin X, Wang R, Wu X, Liu H, Zhang C, Zhao W, Yu F. Bio-orthogonal-labeled exosomes reveals specific distribution in vivo and provides potential application in ARDS therapy. Biomaterials 2025; 319:123208. [PMID: 40023928 DOI: 10.1016/j.biomaterials.2025.123208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/15/2025] [Accepted: 02/23/2025] [Indexed: 03/04/2025]
Abstract
Exosomes derived from specific cells may be useful for targeted drug delivery, but tracking them in vivo is essential for their clinical application. However, their small size and complex structure challenge the development of exosome-tracking techniques, and traditional labeling methods are limited by weak affinity and potential toxicity. To address these issues, here we developed a novel bio-orthogonal labeling strategy based on phosphatidylinositol derivatives to fluorescently label exosomes from various human and mouse cell types. The different cell-derived exosomes revealed organ-specific distribution patterns and a favorable safety profile. Notably, 4T1 cell-derived exosomes specifically targeted the lungs. When used as drug carriers loaded with anti-inflammatory resveratrol, these exosomes showed significant therapeutic efficacy in mice with acute respiratory distress syndrome (ARDS), effectively reducing inflammatory responses, mitigating pulmonary fibrosis, and restoring lung tissue morphology and function. Our findings provide a novel exosome labeling strategy and an invaluable tool for their in vivo tracking and targeting screening, while exosomes that specifically target the lungs offer a potential therapeutic strategy for organ-specific diseases such as ARDS.
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Affiliation(s)
- Song Yang
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Haomiao Zhu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China; Department of Pharmacy, Qilu Hospital, Shandong University, No.107 Cultural West Road, Jinan, 250012, China
| | - Hongzhen Jin
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Kun Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Junna Song
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Na Sun
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China
| | - Yonghui Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China; School of Chemistry, Tiangong University, No.399 BinShuiXi Road, Tianjin, 300387, China
| | - Xiaona Yin
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Rui Wang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China
| | - Xiao Wu
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China
| | - Huadong Liu
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China
| | - Chunling Zhang
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China.
| | - Wei Zhao
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China.
| | - Fan Yu
- Qingdao Central Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, No. 369, Qingdao National High-Tech Industrial Development Zone, Qingdao, 266113, China; State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin, Nankai University, No.38 Tongyan Road, Haihe Education Park, Tianjin, 300350, China.
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Yang L, Chen T, Huang Y, Yang Y, Cheng X, Wei F. hnRNPA2B1 promotes the production of exosomal miR-103-3p from endothelial progenitor cells to alleviate macrophage M1 polarization in acute respiratory distress syndrome. Int Immunopharmacol 2025; 158:114830. [PMID: 40381491 DOI: 10.1016/j.intimp.2025.114830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 05/07/2025] [Accepted: 05/07/2025] [Indexed: 05/20/2025]
Abstract
BACKGROUND Macrophage polarization plays a crucial role in acute respiratory distress syndrome (ARDS). Recently, mounting evidence has uncovered that endothelial progenitor cells (EPCs) secreted exosomes (EPCs-Exos) exert obvious therapeutic effects on the pathological inflammatory process of ARDS, but its potential mechanism is rarely reported. METHODS The primary mouse EPCs and EPCs-Exos were isolated and identified. Absorption of EPCs-Exos by RAW264.7 cells was examined by PKH-26 staining. The polarization of RAW264.7 cells was evaluated by flow cytometry and RT-qPCR analysis. Molecular interactions were verified by dual luciferase assay, RNA pull-down and RNA immunocoprecipitation assays. ARDS mouse model was established, and pathological changes and expressions of related molecules were detected by HE staining, RT-qPCR and western blotting. RESULTS EPCs-Exos could be transferred to macrophages, and effectively reversed LPS-induced polarization of macrophages from M2 to M1 phenotype; however, these changes were diminished by activation of TLR4/NF-κB pathway. MiR-103-3p was proved to be enriched in EPC-Exos and could transfer to macrophage and inactivating TLR4/NF-κB pathway via directly binding to TLR4 3'-UTR. Moreover, miR-103-3p overexpression elevated macrophage M2 polarization and repressed M1 polarization in LPS-treated cells by inhibiting TLR4/NF-κB pathway, and knockdown of miR-103-3p in EPC-Exos abolished the regulatory roles of EPC-Exos on macrophage polarization in vitro, and lung inflammatory injury in vivo. HnRNPA2B1 was proved to interact with miR-103-3p and responsible for its exosomal secretion, which repressed pro-inflammatory macrophage polarization. CONCLUSION These findings suggested that hnRNPA2B1-mediated exosomal delivery of miR-103-3p from EPCs protected against macrophage inflammation in ARDS by inactivation of TLR4/NF-κB pathway.
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Affiliation(s)
- Lei Yang
- Department of Gynecology and Obstetrics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, PR China
| | - Ting Chen
- Department of Anesthesiology and Operation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330052, Jiangxi Province, PR China
| | - Yuanlu Huang
- Department of Anesthesiology and Operation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330052, Jiangxi Province, PR China
| | - Yuxuan Yang
- Department of Anesthesiology and Operation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330052, Jiangxi Province, PR China
| | - Xiaoe Cheng
- Department of Anesthesiology and Operation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330052, Jiangxi Province, PR China
| | - Fusheng Wei
- Department of Anesthesiology and Operation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330052, Jiangxi Province, PR China.
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Deng H, Zhou W, Wei J, Jin T, Chen Y, Zhu L, Yang H, Lv X. Bone marrow mesenchymal stem cell-derived exosomes alleviating sepsis-induced lung injury by inhibiting ferroptosis of macrophages. Int Immunopharmacol 2025; 158:114789. [PMID: 40367688 DOI: 10.1016/j.intimp.2025.114789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/30/2025] [Accepted: 04/30/2025] [Indexed: 05/16/2025]
Abstract
OBJECTIVE To investigate whether bone marrow mesenchymal stem cells derived exosomes (BMSCs-exo) can alleviate sepsis-induced lung injury and its related mechanism by inhibiting ferroptosis of macrophages. METHODS RAW264.7 cells were first stimulated with lipopolysaccharide (LPS) to observe whether macrophage ferroptosis occurred. After pre-treating BMSCs with the exosome inhibitor GW4869, the lung-protective effect was observed to determine if it was eliminated. Furthermore, BMSCs-exo was extracted to clarify if it could exert effects like BMSCs. Finally, key molecules responsible for the effects were identified through sequencing and other related techniques. RESULTS Following stimulation with LPS, the expression of GPX4 in RAW264.7 cells decreased significantly, while the expression of PTGS2 increased significantly. The intracellular GSH content decreased, while MDA content increased. BMSCs-exo reversed the decrease in GPX4 and increase in PTGS2, increased GSH and decreased MDA. Sequencing revealed that lncRNA SNHG12 in macrophages was significantly upregulated after co-culture with BMSCs-exo. Knockdown of lncRNA SNHG12 in BMSCs via siRNA resulted in a significant decrease in the inhibitory effect on macrophage ferroptosis both in vivo and in vitro. CONCLUSION BMSCs-exo can inhibit macrophage ferroptosis through lncRNA SNHG12, thereby alleviating the sepsis-induced lung injury and improving the survival rate.
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Affiliation(s)
- Huimin Deng
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China; Shanghai Institute of Acupuncture and Anesthesia, Shanghai, 200433, China
| | - Wenyu Zhou
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China; Shanghai Institute of Acupuncture and Anesthesia, Shanghai, 200433, China
| | - Juan Wei
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China; Shanghai Institute of Acupuncture and Anesthesia, Shanghai, 200433, China
| | - Tian Jin
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China; Shanghai Institute of Acupuncture and Anesthesia, Shanghai, 200433, China
| | - Yuanli Chen
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China; Shanghai Institute of Acupuncture and Anesthesia, Shanghai, 200433, China
| | - Lina Zhu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China; Shanghai Institute of Acupuncture and Anesthesia, Shanghai, 200433, China
| | - Hao Yang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China; Shanghai Institute of Acupuncture and Anesthesia, Shanghai, 200433, China.
| | - Xin Lv
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, China; Shanghai Institute of Acupuncture and Anesthesia, Shanghai, 200433, China.
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5
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Hou FF, Song Y, Du WN, Wang BB, Wang Q, Wu Q, Yan LN, Chen X. Predictive value of red blood cell distribution width in critically ill patients with acute respiratory distress syndrome: A meta-analysis. Medicine (Baltimore) 2025; 104:e42701. [PMID: 40489812 DOI: 10.1097/md.0000000000042701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/11/2025] Open
Abstract
BACKGROUND Critically ill patients with acute respiratory distress syndrome (ARDS) are one of the leading causes of death worldwide. Although a number of relevant predictors of ARDS have been identified, the current predictors are not satisfactory. Recent studies have revealed the predictive value of red blood cell distribution width (RDW) for ARDS. Therefore, we conducted the first meta-analysis to explore the predictive value of RDW in critically ill patients with ARDS. METHODS A literature search was conducted to identify relevant observational studies from January 1, 2000, to August 1, 2024. Eligible studies were screened and data were extracted. The standardized mean difference (SMD) with 95% confidence interval (CI) of the RDW levels for each study were combined under the random-effect model. RESULTS Ten articles with a total of 2252 participants were included in the study. Elevated RDW levels on admission was significantly associated with significantly associated with an increased risk of ARDS morbidity (SMD = 1.09; 95% CI = 0.35-1.82; P = .004), and also significantly associated with an increased risk of ARDS mortality (SMD = 0.73; 95% CI = 0.53-0.93; P < .00001). Subgroup analysis further showed RDW ≥ 14.0 on admission could be regarded as a predictive morbidity factor for ARDS (SMD = 1.36; 95% CI = 0.66-2.07; P = .0002), and RDW ≥ 15.5 on admission could be also regarded as a predictive mortality factor for ARDS (SMD = 0.73; 95% CI = 0.49-0.97; P < .00001). CONCLUSION RDW levels seems to be a useful tool for predicting the morbidity and mortality of critically ill patients with ARDS.
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Affiliation(s)
- Fei-Fei Hou
- Department of Intensive Care Unit, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, P.R. China
| | - Yong Song
- Department of Intensive Care Unit, Zibo Traditional Chinese Medicine Hospital, Zibo, Shandong, P.R. China
| | - Wei-Na Du
- Department of Critical Care Medicine, Huantai County People's Hospital, Zibo, Shandong, P.R. China
| | - Bei-Bei Wang
- Department of Cardiology, The First People's Hospital of Jinzhong, Jinzhong, Shanxi, P.R. China
| | - Qiong Wang
- Department of Plastic Surgery and Burn, Hohhot First Hospital, Hohhot, Inner Mongolia, P.R. China
| | - Qiong Wu
- Department of Intensive Care Unit, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, P.R. China
| | - Li-Na Yan
- Department of Intensive Care Unit, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, P.R. China
| | - Xin Chen
- Department of Intensive Care Unit, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, P.R. China
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Fließer E, Jandl K, Chen SH, Wang MT, Schupp JC, Kuebler WM, Baker AH, Kwapiszewska G. Transcriptional signatures of endothelial cells shape immune responses in cardiopulmonary health and disease. JCI Insight 2025; 10:e191059. [PMID: 40401523 DOI: 10.1172/jci.insight.191059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025] Open
Abstract
The cardiopulmonary vasculature and its associated endothelial cells (ECs) play an essential role in sustaining life by ensuring the delivery of oxygen and nutrients. Beyond these foundational functions, ECs serve as key regulators of immune responses. Recent advances in single-cell RNA sequencing have revealed that the cardiopulmonary vasculature is composed of diverse EC subpopulations, some of which exhibit specialized immunomodulatory properties. Evidence for immunomodulation includes distinct expression profiles associated with antigen presentation, cytokine secretion, immune cell recruitment, translocation, and clearance - functions critical for maintaining homeostasis in the heart and lungs. In cardiopulmonary diseases, ECs undergo substantial transcriptional reprogramming, leading to a shift from homeostasis to an activated state marked by heightened immunomodulatory activity. This transformation has highlighted the critical role for ECs in disease pathogenesis and their potential as future therapy targets. This Review emphasizes the diverse functions of ECs in the heart and lungs, particularly adaptive and maladaptive immunoregulatory roles in cardiopulmonary health and disease.
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Affiliation(s)
- Elisabeth Fließer
- Otto Loewi Research Center, Lung Research Cluster, Medical University of Graz, Graz, Austria
- Institute for Lung Health, Cardiopulmonary Institute, Member of German Lung Center, Justus-Liebig University, Giessen, Germany
| | - Katharina Jandl
- Otto Loewi Research Center, Lung Research Cluster, Medical University of Graz, Graz, Austria
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Shiau-Haln Chen
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
| | - Mei-Tzu Wang
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
- Institute of Emergency and Critical Care Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jonas C Schupp
- Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Pulmonary and Infectious Diseases, Hannover Medical School, Hannover, Germany
- Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), German Center for Lung Research BREATH, Hannover, Germany
| | - Wolfgang M Kuebler
- Institute of Physiology, Charité-Universitätsmedizin, Berlin, Germany
- German Center for Cardiovascular Research, Partner Site Berlin, Berlin, Germany
- German Center for Lung Research, Associated Partner Site Berlin, Berlin, Germany
- Department of Surgery and
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Keenan Research Centre, St Michael's Hospital, Toronto, Ontario, Canada
| | - Andrew H Baker
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
- Department of Pathology, Cardiovascular Research Institute Maastricht, School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
| | - Grazyna Kwapiszewska
- Otto Loewi Research Center, Lung Research Cluster, Medical University of Graz, Graz, Austria
- Institute for Lung Health, Cardiopulmonary Institute, Member of German Lung Center, Justus-Liebig University, Giessen, Germany
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Jiang F, Jiang J, Sun Y, Meng L, Chen J, Liang L, Wang X, Zhang H, Meng M, Yuan B, He S, Li R. Pelargonidin-3- O-galactoside Alleviates Acute Lung Injury Induced by Klebsiella pneumoniae by Targeting CD38-Mediated Pyroptosis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025. [PMID: 40391938 DOI: 10.1021/acs.jafc.4c10129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
Antibiotic resistance has amplified the threat of bacterial-induced acute lung injury (ALI) to human health. In the quest for novel therapeutic strategies, natural products have shown promise in mitigating the severity of this condition. In this study, we explored the protective effects of pelargonidin-3-O-galactoside (Pg3gal) on Klebsiella pneumoniae (KP)-induced ALI and its underlying mechanisms. Our findings indicated that Pg3gal mitigated lung histopathological changes and edema by inhibiting the migration and infiltration of immune cells and by reducing the secretion of pro-inflammatory cytokines. Molecular docking and surface plasmon resonance analyses revealed that Pg3gal bound to CD38 with high affinity. Further investigation showed that Pg3gal downregulated CD38 expression by promoting its ubiquitination. The reduction of CD38 elevated NAD+ levels and SIRT1 expression and inhibited NF-κB p65 acetylation, thereby suppressing NLRP3 inflammasome-mediated pyroptosis. Our research demonstrates that Pg3gal exerts protective effects against KP-induced ALI by inhibiting pyroptosis through the CD38/SIRT1/NF-κB/NLRP3 signaling pathway, highlighting its potential as a therapeutic agent for ALI.
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Affiliation(s)
- Fei Jiang
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
- Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China
| | - Jiebang Jiang
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
| | - Yipeng Sun
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
| | - Li Meng
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
| | - Jing Chen
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
| | - Lulu Liang
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
| | - Xueshuang Wang
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
| | - Huiyan Zhang
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
| | - Mi Meng
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Bo Yuan
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
| | - Sisi He
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Rongpeng Li
- School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, China
- Medical School of Nantong University, Nantong 226001, China
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Pilling D, Consalvo KM, Kirolos SA, Gomer RH. Differences between human male and female neutrophils with respect to which RNAs are present in polysomes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.05.07.652701. [PMID: 40463083 PMCID: PMC12132174 DOI: 10.1101/2025.05.07.652701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/11/2025]
Abstract
Background Human males and females show differences in the incidence of neutrophil-associated diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, and differences in neutrophil physiological responses such as responses to infection, tissue damage, and chemotactic factors. However, little is known about the basis of sex-based differences in human neutrophils. Methods Starting with human neutrophils from healthy donors, we used RNA-seq to examine total RNA profiles, RNAs not associated with ribosomes and thus not being translated, RNAs in monosomes, and RNAs in polysomes and thus heavily translated. Results There were sex-based differences in the levels of RNAs across free RNA, monosome, and polysome fractions. Male neutrophils had increased levels of mRNAs encoding mitochondrial proteins in the free RNA fractions, indicating low levels of translation. The polysomes of male neutrophils were enriched for mRNAs encoding cytoskeletal organization, cell motility, and cell activation. The polysomes of female neutrophils were enriched for mRNAs associated the regulation of metabolic processes, cytokine responses, and mitochondrial proteins. Conclusions These data indicate that male and female neutrophils have different expression patterns and different translation efficiency of some mRNAs. This may contribute to the observed sex-based differences in neutrophil behavior and neutrophil-associated disease incidence and severity.
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Affiliation(s)
| | | | - Sara A. Kirolos
- Department of Biology, Texas A&M University, College Station, TX 77843-3474 USA
| | - Richard H. Gomer
- Department of Biology, Texas A&M University, College Station, TX 77843-3474 USA
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Zhou X, Wang Z, Wang Y, Xu G, Luo M, Zhang M, Li Y. Rutin ameliorates LPS-induced acute lung injury in mice by inhibiting the cGAS-STING-NLRP3 signaling pathway. Front Pharmacol 2025; 16:1590096. [PMID: 40406492 PMCID: PMC12095315 DOI: 10.3389/fphar.2025.1590096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Accepted: 04/22/2025] [Indexed: 05/26/2025] Open
Abstract
Introduction Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), represent critical respiratory failures with high mortality rates and limited treatment options. While the flavonoid rutin exhibits documented anti-inflammatory and antioxidant properties, its therapeutic mechanisms in ALI/ARDS remain unclear. This study investigated rutin's efficacy against lipopolysaccharide (LPS)-induced ALI in mice, with a mechanistic focus on the cGAS-STING pathway and NLRP3 inflammasome activation. Methods Male C57BL/6 mice were divided into Vehicle control, LPS induction, LPS + rutin co-treatment, and Rutin monotherapy groups. ALI was induced by intratracheal LPS challenge, and rutin was administered via gavage. Proteomics analysis, histological evaluation, immunohistochemistry, TUNEL staining, immunofluorescence, RT-qPCR, western blot, ELISA, and oxidative stress assays were performed to assess the effects of rutin on ARDS. Results The proteomic profiling of lung tissues from LPS-challenged mice identified significant dysregulation of proteins integral to the cGAS-STING cascade and pyroptotic processes. Gene ontology and KEGG pathway analyses underscored the pivotal role of immune and inflammatory responses in ALI, particularly in cytosolic DNA-sensing and NOD-like receptor signaling pathways. Rutin administration significantly alleviated LPS-induced lung injury, reducing oxidative stress, apoptosis, and proinflammatory cytokine levels (IL-6, IL-1β, TNF-α). Mechanistically, rutin demonstrated dual suppression: 1) inhibiting cGAS-STING activation through decreased expression of cGAS, STING, and phosphorylation of TBK1/IRF3 (P<0.05), and 2) attenuating NLRP3-mediated pyroptosis via downregulation of NLRP3-ASC-caspase1-GSDMD signaling (P<0.05). Pharmacological STING inhibition (C-176) validated the cGAS-STING-NLRP3 regulatory hierarchy in ALI pathogenesis. Conclusion These findings elucidate rutin's novel therapeutic mechanism through coordinated suppression of the cGAS-STING-NLRP3 axis, positioning it as a promising candidate for ALI/ARDS intervention.
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Affiliation(s)
- Xin Zhou
- Department of Respiratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Zhibin Wang
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yuting Wang
- Department of Respiratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Guofeng Xu
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Min Luo
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Mengwei Zhang
- Department of Respiratory Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yuying Li
- Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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10
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Yu X, Song Y, Dong T, Ouyang W, Quan C, Shao L, Barasa L, Thompson PR, Zhang M, Ma J, Kurabayashi K, Li Y. Citrullination of NF-κB p65 by PAD2 as a Novel Therapeutic Target for Modulating Macrophage Polarization in Acute Lung Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413253. [PMID: 40087815 PMCID: PMC12079445 DOI: 10.1002/advs.202413253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 02/11/2025] [Indexed: 03/17/2025]
Abstract
Mediating protein citrullination, peptidyl arginine deiminase 2 (PAD2) has recently been reported to influence macrophage phenotypes. However, the mechanisms of PAD2 on macrophage function in Pseudomonas aeruginosa (PA)-induced acute lung injury syndrome (ALI) remains unclear. Utilizing single-cell RNA sequencing and mass spectrometry-based proteomics, a new citrullination site at arginine 171 (R171) is discovered within nuclear factor- κB (NF-κB) p65 catalyzed by PAD2, which modulates PAD2-NF-κB p65-importin α3 pathway and its downstream M1/M2 macrophage polarization. Building on these findings, a cell-specific targeted therapeutic strategy using gold nanoparticles (AuNPs) conjugated with a novel PAD2 inhibitor, AFM41a, and an intercellular adhesion molecule-1 (ICAM-1) antibody is developed. This approach enables the selective delivery of the inhibitor to M1-polarized macrophages in the PA-infected alveolar niche. In vivo, this nanomedicine reduces excessive inflammation and promotes M1-to-M2 polarization to inhibit ALI. This study highlights the role of PAD2-mediated citrullination in macrophage polarization and introduces a promising nanoparticle-based therapy for PA-induced ALI.
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Affiliation(s)
- Xin Yu
- Department of SurgeryUniversity of Michigan Health SystemAnn ArborMI48109USA
- Department of Emergency MedicineSecond Affiliated HospitalZhejiang University School of MedicineNo.88 Jiefang RoadHangzhouZhejiang310009China
| | - Yujing Song
- Department of Mechanical and Aerospace EngineeringNew York University Tandon School of EngineeringBrooklynNY11201USA
- Department of Mechanical EngineeringUniversity of MichiganAnn ArborMI48109USA
| | - Tao Dong
- Department of SurgeryUniversity of Michigan Health SystemAnn ArborMI48109USA
- Department of PhysiologyXuzhou Medical UniversityXu ZhouJiangsu221002China
| | - Wenlu Ouyang
- Department of SurgeryUniversity of Michigan Health SystemAnn ArborMI48109USA
- Department of Metabolism and EndocrinologyThe Second Xiangya HospitalChangsha410011China
| | - Chao Quan
- Department of SurgeryUniversity of Michigan Health SystemAnn ArborMI48109USA
- Department of UrologyThe Xiangya HospitalChangsha410013China
| | - Liujiazi Shao
- Department of SurgeryUniversity of Michigan Health SystemAnn ArborMI48109USA
- Department of AnesthesiologyBeijing Friendship HospitalCapital Medical UniversityNo.95 Yong‐an Road, Xicheng DistrictBeijing100050China
| | - Leonard Barasa
- Program in Chemical Biology, Department of Biochemistry and Molecular BiotechnologyUniversity of Massachusetts Chan Medical SchoolWorcesterMA01605USA
| | - Paul R. Thompson
- Program in Chemical Biology, Department of Biochemistry and Molecular BiotechnologyUniversity of Massachusetts Chan Medical SchoolWorcesterMA01605USA
| | - Mao Zhang
- Department of Emergency MedicineSecond Affiliated HospitalZhejiang University School of MedicineNo.88 Jiefang RoadHangzhouZhejiang310009China
| | - Jianjie Ma
- Department of SurgeryDivision of Surgical ScienceUniversity of VirginiaCharlottesvilleVA22903USA
| | - Katsuo Kurabayashi
- Department of Mechanical and Aerospace EngineeringNew York University Tandon School of EngineeringBrooklynNY11201USA
- Department of Chemical and Biomolecular EngineeringNew York University Tandon School of EngineeringBrooklynNY11201USA
| | - Yongqing Li
- Department of SurgeryUniversity of Michigan Health SystemAnn ArborMI48109USA
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11
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Liu X, Huang Y, Zhang H, Yang X, Liu Q, Dai J. Integrating single-cell sequencing and transcriptome analysis to unravel the mechanistic role of sialylation-related genes in sepsis-induced acute respiratory distress syndrome. Front Immunol 2025; 16:1528769. [PMID: 40375981 PMCID: PMC12078151 DOI: 10.3389/fimmu.2025.1528769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 04/01/2025] [Indexed: 05/18/2025] Open
Abstract
Background Studies have shown that sialylation of C1 esterase inhibitors is crucial for their interaction with histones, and histone-C1 esterase inhibitor complexes are detected in acute respiratory distress syndrome (ARDS), suggesting a potential role of sialylation in ARDS. However, the specific function of sialylation in ARDS remains unclear. Therefore, this study aimed to investigate the mechanism of sialylation-related genes (SRGs) in sepsis-induced ARDS. Methods The ARDS related datasets (GSE32707, GSE66890, and GSE151263) were included in this study. Candidate genes were identified by implementing differential expression analysis and weighted gene co-expression network analysis (WGCNA). Subsequently, further selection by machine learning and expression assessment confirmed the key genes related to sialylation in sepsis-induced ARDS. Following this, the predictive ability of key genes as a whole for sepsis-induced ARDS was evaluated by creating a nomogram model. Afterwards, enrichment analysis, construction of regulatory networks, and drug prediction analysis were implemented to further understand the molecular mechanisms of action of key genes. Furthermore, single-cell RNA sequencing (scRNA-seq) data analysis was conducted to obtain key cells. Additionally, cell communication and pseudo-time analyses were implemented. In the end, the expression levels of the key genes were assessed by collecting clinical samples. Results CD19 and GPR65 were identified as key genes associated with sialylation in sepsis-induced ARDS. The constructed nomogram model demonstrated that CD19 and GPR65 as a whole exhibited robust predictive capability for sepsis-induced ARDS. Meanwhile, CD19 and GPR65 were also found to be significantly co-enriched in the apoptosis and B-cell receptor signaling pathway. In addition, some important regulators and drugs with targeting effects on key genes were predicted, such as NEAT1, OIP5-AS1, alprostadil, and tacrolimus. Further, the scRNA-seq data analysis identified nine cell types, among which CD14 monocytes (CD14Mono) was designated as the key cell. Importantly, GPR65 expression exhibited dynamic changes during differentiation of CD14Mono. Also, we found that CD19 was significantly up-regulated in ARDS group. Conclusion We identified CD19 and GPR65 as key genes associated with sialylation in sepsis-induced ARDS, highlighting CD14Mono as key cell type implicated in sepsis-induced ARDS. These findings offered theoretical support for understanding the mechanism of sialylation on sepsis-induced ARDS.
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Affiliation(s)
- Xiaobing Liu
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yake Huang
- Department of Obstetrics and Gynecology, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Hao Zhang
- Department of Critical Care Medicine, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xia Yang
- Department of Wound Infection and Drug, State Key Laboratory of Trauma and Chemical Poisoning, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Quanxing Liu
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jigang Dai
- Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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Cui J, Luo L, Geng H, Gao Y, Chen Y, Yu Q, Huang X, Wang X, Sun T. Proteomics suggests the role of Cxcl12 secreted by hucMSCs in the treatment of lipopolysaccharide-acute lung injury. Microvasc Res 2025; 160:104815. [PMID: 40311750 DOI: 10.1016/j.mvr.2025.104815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 03/28/2025] [Accepted: 04/25/2025] [Indexed: 05/03/2025]
Abstract
Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by a high mortality rate, and its treatment is relatively straightforward. The application of human umbilical cord mesenchymal stem cells (hucMSCs) for the treatment of ARDS has emerged as a novel therapeutic approach and has been the subject of extensive research. In this study, a mouse model of acute lung injury (ALI) was established, and hucMSCs were administered via tail vein injection to investigate the pathogenesis of ARDS and the protein alterations following hucMSC treatment. Data-independent acquisition (DIA) was employed for the proteomic analysis of lung tissue, which included the identification of differentially expressed proteins (DEPs) and their associated pathways. The relevant DEPs identified in the lung tissues of the three groups of mice included Arid5a, Mrpl4, Cxcl12, and Rnf121 (P <0.05). Silencing the expression of Cxcl12 in hucMSCs could significantly inhibit the therapeutic effect of hucMSCs in reducing the permeability of lung tissue and endothelial cells (P < 0.05). Additionally, the signaling pathways associated with the relevant DEPs were analyzed. The DEPs and the enriched pathways discussed herein provide valuable insights into the pathogenesis of ARDS and the potential applications of hucMSCs.
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Affiliation(s)
- Jinfeng Cui
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Liqing Luo
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Hongmei Geng
- Medical Insurance Business Center of Bincheng District Medical Security Bureau, Binzhou City, Shandong Province, China
| | - Yunxiu Gao
- Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Yuanyuan Chen
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Qilin Yu
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Xiao Huang
- Department of Medical Technology, Binzhou Polytechnic, Binzhou, Shandong, China
| | - Xiaozhi Wang
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China.
| | - Ting Sun
- Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China.
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13
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Cui H, Huang X. Multi-omics integration reveals YWHAE as a key mediator of ferroptosis in ARDS. Funct Integr Genomics 2025; 25:94. [PMID: 40261442 DOI: 10.1007/s10142-025-01603-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/08/2025] [Accepted: 04/16/2025] [Indexed: 04/24/2025]
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe hypoxemia and high mortality. Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, has emerged as a critical mechanism in ARDS pathogenesis. However, the molecular regulators of ferroptosis in ARDS remain unclear. This study integrates multi-omics analysis and experimental validation to identify ferroptosis-related targets in ARDS. Bronchoalveolar lavage fluid (BALF) samples from ARDS patients and healthy controls were subjected to proteomics and metabolomics analysis. Transcriptomic data from the GSE243066 dataset and ferroptosis-related gene databases were integrated to identify key genes. Functional enrichment analyses were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. An LPS-induced ARDS mouse model was established for experimental validation, including Western blotting, histopathology, and ferroptosis-related biochemical assays. Multi-omics analysis identified YWHAE as a ferroptosis-associated gene significantly upregulated in ARDS. Functional enrichment revealed key pathways, including ferroptosis, hypoxia-inducible factor-1 signaling, and oxidative stress responses. Proteomic and transcriptomic integration highlighted 51 overlapping differentially expressed genes, with YWHAE emerging as a central hub in the protein-protein interaction network. Metabolomics analysis further revealed glutathione and cysteine metabolism as critical pathways linked to ferroptosis. In the ARDS mouse model, ferroptosis inhibitor ferrostatin-1 (Fer-1) attenuated LPS-induced lung injury, reduced oxidative stress markers, and downregulated YWHAE expression. This study identifies YWHAE as a novel ferroptosis-related target in ARDS through multi-omics analysis and experimental validation. These findings provide new insights into the molecular mechanisms of ferroptosis in ARDS and highlight YWHAE as a potential therapeutic target for future interventions.
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Affiliation(s)
- Honghui Cui
- Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China
- Graduate School of Youjiang, Medical University for Nationalities, Baise, 533000, Guangxi, China
| | - Xia Huang
- Department of Pulmonary and Critical Care Medicine, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.
- Life Science and Clinical Medicine Research Center, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.
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Zhou K, Qin L, Chen Y, Gao H, Ling Y, Qin Q, Mou C, Qin T, Lu J. A machine learning model for predicting acute respiratory distress syndrome risk in patients with sepsis using circulating immune cell parameters: a retrospective study. BMC Infect Dis 2025; 25:568. [PMID: 40259224 PMCID: PMC12013033 DOI: 10.1186/s12879-025-10974-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 04/14/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is a severe complication associated with a high mortality rate in patients with sepsis. Early identification of patients with sepsis at high risk of developing ARDS is crucial for timely intervention, optimization of treatment strategies, and improvement of clinical outcomes. However, traditional risk prediction methods are often insufficient. This study aimed to develop a machine learning (ML) model to predict the risk of ARDS in patients with sepsis using circulating immune cell parameters and other physiological data. METHODS Clinical data from 10,559 patients with sepsis were obtained from the MIMIC-IV database. Principal component analysis (PCA) was used for dimensionality reduction and to comprehensively evaluate the models' predictive capabilities, we used several ML algorithms, including decision trees, k-nearest neighbors (KNN), logistic regression, naive Bayes, random forests, neural networks, XGBoost, and support vector machines (SVM) to predict ARDS risk. The model performance was assessed using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and F1 score. Shapley additive explanations (SHAP) were used to interpret the contribution of individual features to model predictions. RESULTS Among all models, XGBoost showed the best performance with an AUC of 0.764. Feature importance analysis revealed that mean arterial pressure, monocyte count, neutrophil count, pH, and platelet count were key predictors of ARDS risk in patients with sepsis. The SHAP analysis provided further information on how these features contributed to the model's predictions, aiding in interpretability and potential clinical applications. CONCLUSION The XGBoost model using circulating immune cell parameters accurately predicted the risk of ARDS in patients with sepsis. This model could be a useful tool for the early identification of high-risk patients and timely intervention; however, further validation and integration into clinical practice are required.
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Affiliation(s)
- Kaihuan Zhou
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Road, Nanning, 530007, Guangxi, China
| | - Lian Qin
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Road, Nanning, 530007, Guangxi, China
| | - Yin Chen
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Road, Nanning, 530007, Guangxi, China
| | - Hanming Gao
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Road, Nanning, 530007, Guangxi, China
| | - Yicong Ling
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Road, Nanning, 530007, Guangxi, China
| | - Qianqian Qin
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Road, Nanning, 530007, Guangxi, China
| | - Chenglin Mou
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Road, Nanning, 530007, Guangxi, China
| | - Tao Qin
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Road, Nanning, 530007, Guangxi, China.
| | - Junyu Lu
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, No 166 Daxuedong Road, Nanning, 530007, Guangxi, China.
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Mamizu H, Tsuji J, Kumagai M, Kuwana C, Miyagatani M, Mamizu M, Ishikawa D, Kawakami H, Furukawa T, Ishida T, Kaneko C, Sakai T. An autopsy for persistent coronavirus disease 2019 pneumonia during follicular lymphoma treatment: A case report. Intern Med 2025:5283-25. [PMID: 40254437 DOI: 10.2169/internalmedicine.5283-25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/22/2025] Open
Abstract
A 66-year-old man who was receiving treatment for B-cell non-Hodgkin lymphoma presented with fever. He tested positive for severe acute respiratory syndrome coronavirus 2 antigen. Chest computed tomography (CT) revealed pneumonia. Therefore, remdesivir was administered to the patient. However, steroid pulse therapy was initiated owing to the lack of any symptom improvement and a worsening of the CT findings. The patient developed recurrent fever following a reduction in the steroid dose. His respiratory condition gradually worsened, and he eventually died. Autopsy revealed diffuse alveolar damage. In high-risk patients with hematologic malignancy, COVID-19 vaccination should be repeated at shorter intervals to avoid increasing the viral load during the COVID-19 infection.
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Affiliation(s)
- Hikaru Mamizu
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Jun Tsuji
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Morihiro Kumagai
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Chika Kuwana
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Masanori Miyagatani
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Maiko Mamizu
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Daisuke Ishikawa
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Hidenori Kawakami
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Toshiki Furukawa
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Takashi Ishida
- Department of Internal Medicine, Niigata Prefectural Central Hospital, Japan
| | - Chizuru Kaneko
- Department of Diagnostic Pathology, Niigata Prefectural Central Hospital, Japan
| | - Takeshi Sakai
- Department of Diagnostic Pathology, Niigata Prefectural Central Hospital, Japan
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Shi Q, Liu H, Wang H, Tang L, Di Q, Wang D. MFGE8 regulates the EndoMT of HLMECs through the BMP signaling pathway and fibrosis in acute lung injury. Respir Res 2025; 26:142. [PMID: 40223052 PMCID: PMC11995649 DOI: 10.1186/s12931-025-03215-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 04/01/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND To investigate the effects and mechanisms of MFGE8 on LPS-induced endothelial-to-mesenchymal transition (EndoMT) and pulmonary fibrosis in human lung microvascular endothelial cells (HLMECs) and a mouse model of acute lung injury. METHODS Serum MFGE8 levels were compared between ARDS patients and controls. In vitro, HLMECs were treated with LPS, siRNA targeting MFGE8, and recombinant human MFGE8 (rhMFGE8).HLMEC morphology, invasion, migration, and EndoMT markers (CD31, ɑ-SMA) were evaluated. BMP/Smad1/5-Smad4 signaling and Snail expression were assessed via immunofluorescence, western blotting, and qRT-PCR. In vivo, rhMFGE8 effects on pulmonary fibrosis and EndoMT were analyzed in a mouse model of acute lung injury. RESULTS MFGE8 levels were significantly reduced in ARDS patients, with higher levels correlating to better survival. In vitro, rhMFGE8 improved HLMEC morphology, reduced invasion and migration, and attenuated LPS-induced EndoMT by increasing CD31 and decreasing α-SMA. MFGE8 knockdown increased BMP/Smad1/5-Smad4 signaling and Snail expression, while rhMFGE8 inhibited these effects. In vivo, rhMFGE8 ameliorated pulmonary fibrosis and EndoMT in mice. CONCLUSIONS MFGE8 regulates LPS-induced EndoMT in HLMECs via the BMP/Smad1/5-Smad4 pathway and protects against pulmonary fibrosis in acute lung injury, suggesting it as a therapeutic target for ALI and ARDS.
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Affiliation(s)
- Qingqiang Shi
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Huang Liu
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Hanghang Wang
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Ling Tang
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Qi Di
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Daoxin Wang
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Gao R, Zhang X, Ju H, Zhou Y, Yin L, Yang L, Wu P, Sun X, Fang H. Telocyte-derived exosomes promote angiogenesis and alleviate acute respiratory distress syndrome via JAK/STAT-miR-221-E2F2 axis. MOLECULAR BIOMEDICINE 2025; 6:21. [PMID: 40198510 PMCID: PMC11979044 DOI: 10.1186/s43556-025-00259-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 02/27/2025] [Accepted: 03/06/2025] [Indexed: 04/10/2025] Open
Abstract
Acute respiratory distress syndrome (ARDS) is characterized by severe respiratory failure and significant inflammation, leading to vascular and epithelial cell damage. The absence of effective pharmacologic treatments underscores the need for novel therapeutic approaches. Telocytes (TCs), a newly identified type of interstitial cells, have shown potential in tissue repair and angiogenesis, particularly through the release of exosomal microRNAs (miRNAs). Exosomes were isolated from LPS (lipopolysaccharide)-stimulated TCs and characterized using western blotting and nanoparticle tracking analysis. The role of exosomal miR-221 in angiogenesis was assessed through tube formation, migration, and proliferation assays in mouse vascular endothelial cells (MVECs). The JAK/STAT pathway's involvement in miR-221 regulation was determined using western blotting and qRT-PCR. A dual-luciferase assay confirmed E2F2 as a direct target of miR-221. ARDS mouse model was established via LPS instillation, and the therapeutic effects of TCs-derived exosomes were evaluated by histopathological scoring, cytokine analysis, and endothelial barrier integrity assays. Our findings demonstrated that exosomes from LPS-stimulated TCs significantly promoted angiogenesis, proliferation, and migration in MVECs. These effects were mediated by miR-221, which downregulated E2F2 expression, an important regulator of endothelial cell functions. The JAK/STAT pathway played a crucial role in miR-221 production, with pathway inhibition reducing miR-221 levels and attenuating its pro-angiogenic effects. In vivo, TCs-derived exosomes reduced lung inflammation and tissue damage in ARDS mice, effects that were reversed by miR-221 inhibition. These results suggested that TCs-derived exosomes promoted angiogenesis and alleviated ARDS through the JAK/STAT-miR-221-E2F2 axis.
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Affiliation(s)
- Rongrong Gao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Clinical Center for Biotherapy at Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xu Zhang
- NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
- Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China
| | - Huihui Ju
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yile Zhou
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Luoyue Yin
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liuke Yang
- College of Plant Protection, Nanjing Agricultural University, Nanjing, 210000, China
| | - Pinwen Wu
- Department of Anesthesiology, Minhang Hospital, Fudan University, Shanghai, China
| | - Xia Sun
- Department of Anesthesiology, Shanghai Geriatric Medical Center, Shanghai, China.
| | - Hao Fang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
- Department of Anesthesiology, Shanghai Geriatric Medical Center, Shanghai, China.
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Kang ZY, Xuan NX, Zhou QC, Huang QY, Yu MJ, Zhang GS, Cui W, Zhang ZC, Du Y, Tian BP. Targeting alveolar epithelial cells with lipid micelle-encapsulated necroptosis inhibitors to alleviate acute lung injury. Commun Biol 2025; 8:573. [PMID: 40188179 PMCID: PMC11972349 DOI: 10.1038/s42003-025-08010-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 03/27/2025] [Indexed: 04/07/2025] Open
Abstract
Acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS), represents a critical condition characterized by extensive inflammation within the airways. Necroptosis, a form of cell death, has been implicated in the pathogenesis of various inflammatory diseases. However, the precise characteristics and mechanisms of necroptosis in ARDS remain unclear. Thus, our study seeks to elucidate the specific alterations and regulatory factors associated with necroptosis in ARDS and to identify potential therapeutic targets for the disease. We discovered that necroptosis mediates the progression of ALI through the activation and formation of the RIPK1/RIPK3/MLKL complex. Moreover, we substantiated the involvement of both MYD88 and TRIF in the activation of the TLR4 signaling pathway in ALI. Furthermore, we have developed a lipid micelle-encapsulated drug targeting MLKL in alveolar type II epithelial cells and successfully applied it to treat ALI in mice. This targeted nanoparticle selectively inhibited necroptosis, thereby mitigating epithelial cell damage and reducing inflammatory injury. Our study delves into the specific mechanisms of necroptosis in ALI and proposes novel targeted therapeutic agents, presenting innovative strategies for the management of ARDS.
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Affiliation(s)
- Zhi-Ying Kang
- Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Nan-Xia Xuan
- Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Qi-Chao Zhou
- Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Qian-Yu Huang
- Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Meng-Jia Yu
- Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Gen-Sheng Zhang
- Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Wei Cui
- Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Zhao-Cai Zhang
- Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
| | - Yang Du
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
| | - Bao-Ping Tian
- Department of Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
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Cao T, Li AQ, Zhang Y, Xie TT, Weng DZ, Pan CS, Yan L, Sun K, Wang D, Han JY, Liu J. Norwogonin attenuates LPS-induced acute lung injury through inhibiting Src/AKT1/NF-κB signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156432. [PMID: 39922147 DOI: 10.1016/j.phymed.2025.156432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 01/14/2025] [Accepted: 01/25/2025] [Indexed: 02/10/2025]
Abstract
BACKGROUND Acute lung injury (ALI) has emerged as a critical illness, with sepsis-related ALI accounting for >80 %. In the context of bacterial infection, damage to the pulmonary microvascular barrier leads to inflammatory cell infiltration and plasma component extravasation into pulmonary interstitium. This disruption impairs gas exchange, resulting in hypoxemia. Norwogonin (NWG), a natural plant flavone, has shown potential anti-inflammatory and antioxidative effects. However, whether it could ameliorate sepsis-related ALI and the potential mechanism remains unknown. PURPOSE This study aims to investigate the effects and underlying mechanisms of NWG in treating sepsis-related ALI. METHODS Male Wistar rats (200-220 g) were used to establish sepsis-related ALI model via intraperitoneal injection of lipopolysaccharide (LPS). Vital signs and arterial blood gas analysis, HE and immunohistochemistry staining, dynamic visualization of the microcirculatory system to observe FITC-dextran leakage and leukocyte adhesion, ELISA assay of inflammatory cytokines, Evans Blue extravasation, measurement of total protein content in bronchoalveolar lavage fluid, determination of the Wet/Dry weight ratio, Western blot and RT-qPCR analysis were used to evaluate NWG's effects and the potential mechanism. Additionally, we employed network pharmacology and molecular docking to identify and evaluate the interaction between NWG and the key targets of ALI. Surface plasmon resonance and enzyme activity assay were utilized to confirm the direct interaction between NWG and the potential targets. RESULTS NWG administration improved the vital signs of LPS-stimulated rats. Exposure to LPS led to deteriorated arterial blood gas analysis, prominent lung morphology destruction, neutrophil and M1 macrophage infiltration, leukocyte adhesion, FITC-dextran leakage, elevated secretion of inflammatory cytokines, and aggravated lung edema. NWG intervention effectively mitigated these changes. Furthermore, NWG suppressed NF-κB/NLRP3 signaling and up-regulated endothelial junction proteins. Network pharmacology analysis and molecular docking identified five top key targets: MMP-9, AKT1, COX-2, Src and JAK-2. Western blot and RT-qPCR results confirmed that NWG inhibited the Src/AKT1/NF-κB signaling pathway, and down-regulated the levels of inflammatory factors. Surface plasmon resonance revealed the direct binding between NWG and AKT1, COX-2 and Src, rather than MMP-9. Enzyme activity assay demonstrated that NWG inhibited the activity of AKT1, COX-2 and Src. CONCLUSION NWG alleviated inflammation, restored pulmonary microvascular barrier function and improved LPS-induced ALI. These effects were mediated by inhibiting the Src/AKT1/NF-κB signaling pathway through direct targeting of Src, AKT1 and COX-2. Our study provided novel scientific evidence supporting the use of NWG in the treatment of ALI caused by sepsis.
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Affiliation(s)
- Tianjiao Cao
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, PR China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Health Science Center, Peking University, Beijing, PR China
| | - An-Qing Li
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, PR China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China
| | - Yi Zhang
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, PR China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China
| | - Ting-Ting Xie
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, PR China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China
| | - Ding-Zhou Weng
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, PR China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China
| | - Chun-Shui Pan
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China
| | - Li Yan
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China
| | - Kai Sun
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China
| | - Di Wang
- Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, PR China
| | - Jing-Yan Han
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, PR China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China.
| | - Jian Liu
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, PR China; Academy of Integration of Chinese and Western Medicine, Peking University Health Science Center, Beijing, PR China; The Key Discipline for Integration of Chinese and Western Basic Medicine (Microcirculation) of the National Administration of Traditional Chinese Medicine, Beijing, PR China; Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, PR China; State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tianjin, PR China; Beijing Microvascular Institute of Integration of Chinese and Western Medicine, Beijing, PR China.
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20
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Traber KE, Mizgerd JP. The Integrated Pulmonary Immune Response to Pneumonia. Annu Rev Immunol 2025; 43:545-569. [PMID: 40036700 DOI: 10.1146/annurev-immunol-082323-031642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
Pneumonia is an acute respiratory infection of the lower respiratory tract. The effectiveness of the host immune response determines the severity of infection, or whether pneumonia occurs at all. The lungs house both innate and adaptive immune systems, which integrate their activities to provide host defense that eliminates microbes and prevents lower respiratory infection from becoming severe. Professional immune cells in the lung, like macrophages and lymphocytes, work with lung constituents, like epithelial cells and fibroblasts, to optimize antimicrobial defense. The dynamics of the immune response during infection and the immune components contributing to defense are influenced by prior experiences with respiratory pathogens, remodeling lung immunity in ways that improve responses against subsequent infections. This review covers how innate and adaptive immune activities coordinate inside the lung to provide integrated and effective immune resistance against respiratory pathogens.
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Affiliation(s)
- Katrina E Traber
- Pulmonary Center and Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA;
| | - Joseph P Mizgerd
- Pulmonary Center and Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA;
- Department of Virology, Immunology, and Microbiology and Department of Biochemistry and Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
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21
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Ng YY, Ho YC, Yen CH, Lee SS, Tseng CC, Wu SW, Kuan YH. Protective Effect of Hibifolin on Lipopolysaccharide-Induced Acute Lung Injury Through Akt Phosphorylation and NFκB Pathway. ENVIRONMENTAL TOXICOLOGY 2025; 40:524-531. [PMID: 39119817 DOI: 10.1002/tox.24383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/08/2024] [Accepted: 05/23/2024] [Indexed: 08/10/2024]
Abstract
Acute lung injury (ALI) is a difficult condition to manage, especially when it is complicated by bacterial sepsis. Hibifolin, a flavonoid glycoside, has anti-inflammatory properties that make it a potential treatment for ALI. However, more research is needed to determine its effectiveness in LPS-induced ALI. In this study, male ICR mice were treated with hibifolin before LPS-induced ALI. Protein content and neutrophil count in bronchoalveolar lavage (BAL) fluid were measured by BCA assay and Giemsa staining method, respectively. The levels of proinflammatory cytokines and adhesive molecules were detected by ELISA assay. The expression of NFκB p65 phosphorylation, IκB degradation, and Akt phosphorylation was assessed by western blot assay. Hibifolin pre-treatment significantly reduced pulmonary vascular barrier dysfunction and neutrophil infiltration into the BAL fluid in LPS-induced ALI mice. In addition, LPS-induced expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α) and adhesive molecules (ICAM-1, VCAM-1) within the BAL fluid were markedly reduced by hibifolin in LPS-induced ALI mice. More, hibifolin inhibited LPS-induced phosphorylation of NFκB p65, degradation of IκB, and phosphorylation of Akt in lungs with ALI mice. In conclusion, hibifolin shows promise in improving the pathophysiological features and proinflammatory responses of LPS-induced ALI in mice through the NFκB pathway and its upstream factor, Akt phosphorylation.
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Affiliation(s)
- Yan-Yan Ng
- Department of Pediatric, Chung Kang Branch, Cheng Ching Hospital, Taichung, Taiwan
| | - Yung-Chuan Ho
- Center for General Education, Chung Shan Medical University, Taichung, Taiwan
| | - Chi-Hua Yen
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Family and Community Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shiuan-Shinn Lee
- School of Public Health, Chung Shan Medical University, Taichung, Taiwan
| | - Ching-Chi Tseng
- Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
- Department of Dermatology, Shiso Municipal Hospital, Shiso, Hyogo, Japan
| | - Sheng-Wen Wu
- Division of Nephrology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- Department of Internal Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Yu-Hsiang Kuan
- Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan
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22
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Mohammadi A, De Luca D, Gauda EB. Characteristics, triggers, treatments, and experimental models of neonatal acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2025; 328:L512-L525. [PMID: 39924963 DOI: 10.1152/ajplung.00312.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/20/2024] [Accepted: 02/04/2025] [Indexed: 02/11/2025] Open
Abstract
Neonatal acute respiratory distress syndrome (NARDS) is a severe and potentially life-threatening form of lung injury recently defined by the International Neonatal ARDS Consensus. It is marked by extensive lung inflammation and damage to the alveolar epithelium and vascular endothelium. NARDS can be triggered by direct inflammatory exposures, such as pneumonia and aspiration, and indirect exposures, including sepsis, necrotizing enterocolitis, and chorioamnionitis. This review provides clinicians and researchers with the latest insights on NARDS. We adopt a cross-disciplinary approach to discuss the diagnostic criteria, pathobiology, triggers, epidemiology, and treatments of NARDS. In addition, we summarize existing clinical studies and advanced preclinical models that help address current knowledge gaps. Future research should focus on standardizing the Montreux consensus definition of NARDS in preclinical and clinical studies, identifying biomarkers, developing prediction models, and exploring novel therapies for affected infants.
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Affiliation(s)
- Atefeh Mohammadi
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Division of Neonatology and Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Daniele De Luca
- Division of Pediatrics and Neonatal Critical Care, "A. Béclère" Medical Center, Paris - Saclay University Hospitals, APHP, Paris, France
- Physiopathology and Therapeutic Innovation Unit-INSERM U999, Paris Saclay University, Paris, France
| | - Estelle B Gauda
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Division of Neonatology and Translational Medicine Program, The Hospital for Sick Children, Toronto, Ontario, Canada
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23
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Bay P, de Prost N. Diagnostic approach in acute hypoxemic respiratory failure. JOURNAL OF INTENSIVE MEDICINE 2025; 5:119-126. [PMID: 40241832 PMCID: PMC11997604 DOI: 10.1016/j.jointm.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/11/2024] [Accepted: 09/23/2024] [Indexed: 04/18/2025]
Abstract
Acute hypoxemic respiratory failure (AHRF) is the leading cause of intensive care unit (ICU) admissions. Of patients with AHRF, 40 %-50 % will require invasive mechanical ventilation during their stay in the ICU, and 30 %-80 % will meet the Berlin Criteria for Acute Respiratory Distress Syndrome (ARDS). Rapid identification of the underlying cause of AHRF is necessary before initiating targeted treatment. Almost 10 % of patients with ARDS have no identified classic risk factors however, and the precise cause of AHRF may not be identified in up to 15 % of patients, particularly in cases of immunosuppression. In these patients, a multidisciplinary, comprehensive, and hierarchical diagnostic work-up is mandatory, including a detailed history and physical examination, chest computed tomography, extensive microbiological investigations, bronchoalveolar lavage fluid cytological analysis, immunological tests, and investigation of the possible involvement of pneumotoxic drugs.
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Affiliation(s)
- Pierre Bay
- Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, Assistance Publique – Hôpitaux de Paris (AP-HP), Créteil, France
- Groupe de Recherche Clinique CARMAS, Université Paris-Est-Créteil (UPEC), Créteil, France
- Université Paris-Est-Créteil (UPEC), Créteil, France
- IMRB INSERM U955, Team “Viruses, Hepatology, Cancer”, Créteil, France
| | - Nicolas de Prost
- Médecine Intensive Réanimation, Hôpitaux Universitaires Henri Mondor, Assistance Publique – Hôpitaux de Paris (AP-HP), Créteil, France
- Groupe de Recherche Clinique CARMAS, Université Paris-Est-Créteil (UPEC), Créteil, France
- Université Paris-Est-Créteil (UPEC), Créteil, France
- IMRB INSERM U955, Team “Viruses, Hepatology, Cancer”, Créteil, France
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Shi J, Tang J, Liu L, Zhang C, Chen W, Qi M, Han Z, Chen X. Integrative Analyses of Bulk and Single-Cell RNA Seq Identified the Shared Genes in Acute Respiratory Distress Syndrome and Rheumatoid Arthritis. Mol Biotechnol 2025; 67:1565-1583. [PMID: 38656728 DOI: 10.1007/s12033-024-01141-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/06/2024] [Indexed: 04/26/2024]
Abstract
Acute respiratory distress syndrome (ARDS), a progressive status of acute lung injury (ALI), is primarily caused by an immune-mediated inflammatory disorder, which can be an acute pulmonary complication of rheumatoid arthritis (RA). As a chronic inflammatory disease regulated by the immune system, RA is closely associated with the occurrence and progression of respiratory diseases. However, it remains elusive whether there are shared genes between the molecular mechanisms underlying RA and ARDS. The objective of this study is to identify potential shared genes for further clinical drug discovery through integrated analysis of bulk RNA sequencing datasets obtained from the Gene Expression Omnibus database, employing differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA). The hub genes were identified through the intersection of common DEGs and WGCNA-derived genes. The Random Forest (RF) and least absolute shrinkage and selection operator (LASSO) algorithms were subsequently employed to identify key shared target genes associated with two diseases. Additionally, RA immune infiltration analysis and COVID-19 single-cell transcriptome analysis revealed the correlation between these key genes and immune cells. A total of 59 shared genes were identified from the intersection of DEGs and gene clusters obtained through WGCNA, which analyzed the integrated gene matrix of ALI/ARDS and RA. The RF and LASSO algorithms were employed to screen for target genes specific to ALI/ARDS and RA, respectively. The final set of overlapping genes (FCMR, ADAM28, HK3, GRB10, UBE2J1, HPSE, DDX24, BATF, and CST7) all exhibited a strong predictive effect with an area under the curve (AUC) value greater than 0.8. Then, the immune infiltration analysis revealed a strong correlation between UBE2J1 and plasma cells in RA. Furthermore, scRNA-seq analysis demonstrated differential expression of these nine target genes primarily in T cells and NK cells, with CST7 showing a significant positive correlation specifically with NK cells. Beyond that, transcriptome sequencing was conducted on lung tissue collected from ALI mice, confirming the substantial differential expression of FCMR, HK3, UBE2J1, and BATF. This study provides unprecedented evidence linking the pathophysiological mechanisms of ALI/ARDS and RA to immune regulation, which offers novel understanding for future clinical treatment and experimental research.
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Affiliation(s)
- Jun Shi
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Jiajia Tang
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Lu Liu
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Chunyang Zhang
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Wei Chen
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Man Qi
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China
| | - Zhihai Han
- School of Medicine, South China University of Technology, Guangzhou, 510006, China.
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China.
| | - Xuxin Chen
- School of Medicine, South China University of Technology, Guangzhou, 510006, China.
- Department of Pulmonary and Critical Care Medicine, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China.
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25
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Xuan W, Liang C, Yang S, Zheng L, Wu X, Zhang X. FABP4 expression in neutrophils as a predictor of sepsis and SI-ARDS based on BALF transcriptome and peripheral blood validation. Chin Med J (Engl) 2025:00029330-990000000-01499. [PMID: 40169352 DOI: 10.1097/cm9.0000000000003447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Indexed: 04/03/2025] Open
Abstract
BACKGROUND The objective of this study is to delineate the differential gene expression patterns of neutrophils in bronchoalveolar lavage fluid (BALF) from patients with sepsis and those experiencing progression to sepsis-induced acute respiratory distress syndrome (SI-ARDS). Additionally, we aim to comprehensively profile the transcriptomic landscape of neutrophils in BALF from patients with sepsis and SI-ARDS, particularly focusing on cases caused by specific bacterial pathogens. METHODS Patients with confirmed sepsis (n = 14) or SI-ARDS (n = 11) were recruited. Besides, a control group consisting of patients with unrelated diseases (n = 7) who required bronchoscopy was also included (cohort 1). We collected the neutrophils in BALF from participants in cohort 1. To validate the identified differentially expressed genes (DEGs) and evaluate neutrophil apoptosis, an additional cohort (cohort 2) was recruited, consisting of 5 healthy controls, 10 patients with sepsis, and 10 patients with SI-ARDS. Peripheral blood neutrophils were collected from participants in cohort 2 for further analysis. DEGs between SI-ARDS patients and controls, sepsis patients and controls, as well as SI-ARDS patients and sepsis patients were identified. And, publicly available datasets were downloaded to compare with local results. Additionally, the DEGs were also identified between patients infected with drug-resistant Klebsiella pneumoniae and those infected with other bacterial pathogens. Furthermore, a third cohort (cohort 3) consisting of 57 sepsis patients and 46 SI-ARDS patients was recruited for investigating the prognostic significance of neutrophils in SI-ARDS. RESULTS In cohort 1, 8/14 of the septic patients and 6/11 of the SI-ARDS patients were affected by drug-resistant Klebsiella pneumonia. There were 9921 DEGs between sepsis patients and controls, 10,252 DEGs between SI-ARDS patients and controls, and 24 DEGs between SI-ARDS and sepsis patients in neutrophils from BALF. Notably, fatty acid-binding pro-tein 4 (FABP4) exhibited significant downregulation in SI-ARDS patients. In cohort 2, peripheral blood analysis confirmed consistent trends, demonstrating that FABP4 expression was decreased, which contributed to the attenuation of neutrophil apoptosis. And FABP4 inhibitor-induced apoptosis resistance was reversed by a phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) inhibitor. Furthermore, survival analysis revealed that SI-ARDS patients with low levels of neutrophil FABP4 expression exhibited poor survival. Additionally, 520 overlapping DEGs were identified between the sepsis and control group comparisons and the SI-ARDS and sepsis group comparisons. Among these overlapping DEGs, 85% were downregulated, predominantly targeting immune-related pathways, whereas a smaller subset was upregulated, mainly associated with metabolism. DEGs in neutrophils in BALF of SI-ARDS and controls notably overlapped with those in neutrophils in peripheral blood. Importantly, DEGs in sepsis/SI-ARDS caused by drug-resistant Klebsiella pneumoniae differed from DEGs in sepsis/SI-ARDS caused by other bacteria. Additionally, FABP4 expression consistently decreased, attenuating neutrophil apoptosis. CONCLUSIONS The downregulation of FABP4 in neutrophils was found to inhibit apoptosis through the activation of the PI3K/AKT signaling pathway. Importantly, the expression level of FABP4 in neutrophil emerged as a prognostic indicator for sepsis and SI-ARDS patients, suggesting its potential utility in clinical decision-making to address the challenges posed by this condition.
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Affiliation(s)
- Weixia Xuan
- Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing 100000, China
- Department of Pulmonary and Critical Care Medicine, National Center for Respiratory Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing 100000, China
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
| | - Chaofan Liang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
| | - Shenying Yang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
| | - Longcheng Zheng
- Department of Respiratory and Critical Care Medicine, People's Hospital of Henan University, People's Hospital of Henan Province, Zhengzhou, Henan 450003, China
| | - Xu Wu
- Department of Scientific Research, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 41000, China
| | - Xiaoju Zhang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
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Deniau B, Ludes PO, Khalifeh-Ballan P, Fenninger L, Kindo M, Collange O, Geny B, Noll E, Azibani F, Mebazaa A, Pottecher J. Transpulmonary LOX-1 Levels Are Predictive of Acute Respiratory Distress Syndrome After Cardiac Surgery: A Proof-of-Concept Study. Biomedicines 2025; 13:800. [PMID: 40299349 PMCID: PMC12024757 DOI: 10.3390/biomedicines13040800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/19/2025] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Background/Objectives: Acute respiratory distress syndrome (ARDS) is a life-threatening condition that frequently complicates high-risk cardiac surgery. We evaluated the circulating levels and transpulmonary gradient of intracellular proteins in patients at risk of developing ARDS after cardiac surgery using large scale-proteomics. Methods: We enrolled sixteen patients undergoing high-risk cardiac surgery, followed by planned ICU admission. Circulating levels of intracellular proteins were measured at the onset of the surgical procedure, at ICU admission (H0), and 24 h (H24) after surgery in blood samples simultaneously drawn from both the pulmonary artery and the left atrium. The primary endpoint was the occurrence of ARDS between ICU admission and the subsequent 48 h. Results: Among the studied proteins, the levels of intracellular lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were higher at H24 in the pulmonary artery in patients who developed ARDS (6.96; 95% CI [6.83-7.23]) compared to patients who did not (6.48; 95% CI [6.27-6.66]), p-value = 0.016. The transpulmonary gradient of intracellular LOX-1 levels was not significantly different between ARDS and non-ARDS patients at H0 but it was more negative at H24 in ARDS (-0.23; 95% CI [-0.27, -0.14]) than in non-ARDS patients (0.03; 95% CI [-0.14, 0.32]; p-value= 0.031), with a hazard ratio HR = 0.39 (95% CI [0.18-0.86]); p-value= 0.035. The area under the ROC curve of H24 LOX-1 transpulmonary gradient to predict ARDS occurrence was 0.83 (95% CI [0.62-1.00]). Conclusions: The transpulmonary gradient of intracellular LOX-1 levels was negatively associated with the occurrence of ARDS within the first 48 h after high-risk cardiac surgery, suggesting that lung trapping of LOX-1 may be linked to postoperative ARDS.
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Affiliation(s)
- Benjamin Deniau
- Department of Anaesthesia, Burn and Critical Care, University Hospitals Saint-Louis-Lariboisière, AP-HP, 75010 Paris, France; (B.D.); (A.M.)
- UMR-S 942, INSERM, MASCOT, Paris University, 75018 Paris, France;
- Department of Medicine, Paris Cité University, 75006 Paris, France
- FHU PROMICE, Hôpital Lariboisière 2, rue Ambroise Paré, 75475 Paris, CEDEX 10, France
- INI CRCT, CHRU Brabois, 54500 Vandoeuvre les Nancy, France
| | - Pierre-Olivier Ludes
- Department of Anaesthesiology Critical Care and Perioperative Medicine, Hautepierre Hospital, Strasbourg University Hospital, 67000 Strasbourg, France (P.K.-B.); (L.F.); (E.N.)
| | - Pamela Khalifeh-Ballan
- Department of Anaesthesiology Critical Care and Perioperative Medicine, Hautepierre Hospital, Strasbourg University Hospital, 67000 Strasbourg, France (P.K.-B.); (L.F.); (E.N.)
| | - Luc Fenninger
- Department of Anaesthesiology Critical Care and Perioperative Medicine, Hautepierre Hospital, Strasbourg University Hospital, 67000 Strasbourg, France (P.K.-B.); (L.F.); (E.N.)
| | - Michel Kindo
- Department of CardioVascular Surgery, Nouvel Hôpital Civil, Strasbourg University Hospital, 67000 Strasbourg, France;
- UR 3072, « Mitochondrie, Stress Oxydant et Protection Musculaire », FMTS, FHU Omicare, Faculty of Medicine, Midwifery and Health Sciences, Strasbourg University, 67081 Strasbourg, France; (O.C.); (B.G.)
| | - Olivier Collange
- UR 3072, « Mitochondrie, Stress Oxydant et Protection Musculaire », FMTS, FHU Omicare, Faculty of Medicine, Midwifery and Health Sciences, Strasbourg University, 67081 Strasbourg, France; (O.C.); (B.G.)
- Department of Anaesthesiology Critical Care and Perioperative Medicine, Nouvel Hôpital Civil, Strasbourg University Hospital, 67000 Strasbourg, France
| | - Bernard Geny
- UR 3072, « Mitochondrie, Stress Oxydant et Protection Musculaire », FMTS, FHU Omicare, Faculty of Medicine, Midwifery and Health Sciences, Strasbourg University, 67081 Strasbourg, France; (O.C.); (B.G.)
- Service de Physiologie et d’Explorations Fonctionnelles, Nouvel Hôpital Civil, Strasbourg University Hospital, 67000 Strasbourg, France
| | - Eric Noll
- Department of Anaesthesiology Critical Care and Perioperative Medicine, Hautepierre Hospital, Strasbourg University Hospital, 67000 Strasbourg, France (P.K.-B.); (L.F.); (E.N.)
- UR 3072, « Mitochondrie, Stress Oxydant et Protection Musculaire », FMTS, FHU Omicare, Faculty of Medicine, Midwifery and Health Sciences, Strasbourg University, 67081 Strasbourg, France; (O.C.); (B.G.)
| | - Fériel Azibani
- UMR-S 942, INSERM, MASCOT, Paris University, 75018 Paris, France;
| | - Alexandre Mebazaa
- Department of Anaesthesia, Burn and Critical Care, University Hospitals Saint-Louis-Lariboisière, AP-HP, 75010 Paris, France; (B.D.); (A.M.)
- UMR-S 942, INSERM, MASCOT, Paris University, 75018 Paris, France;
- Department of Medicine, Paris Cité University, 75006 Paris, France
- FHU PROMICE, Hôpital Lariboisière 2, rue Ambroise Paré, 75475 Paris, CEDEX 10, France
- INI CRCT, CHRU Brabois, 54500 Vandoeuvre les Nancy, France
| | - Julien Pottecher
- Department of Anaesthesiology Critical Care and Perioperative Medicine, Hautepierre Hospital, Strasbourg University Hospital, 67000 Strasbourg, France (P.K.-B.); (L.F.); (E.N.)
- UR 3072, « Mitochondrie, Stress Oxydant et Protection Musculaire », FMTS, FHU Omicare, Faculty of Medicine, Midwifery and Health Sciences, Strasbourg University, 67081 Strasbourg, France; (O.C.); (B.G.)
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Xiao Z, Zhou G, Xue H, Chen L, Zhao X, Li S, Fu C, Wang Z, Zhu F. CMTM3 regulates vascular endothelial cell dysfunction by influencing pulmonary vascular endothelial permeability and inflammation in ARDS. Front Immunol 2025; 16:1544610. [PMID: 40196127 PMCID: PMC11973065 DOI: 10.3389/fimmu.2025.1544610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 03/05/2025] [Indexed: 04/09/2025] Open
Abstract
Introduction CMTM3 is a member of the human chemokine-like factor superfamily. The mechanistic role of CMTM3 in acute respiratory distress syndrome (ARDS) is not known. This study investigated the role of CMTM3 in the progression of ARDS and its impact on the function of vascular endothelial cells. Methods ARDS modeling in human umbilical vascular endothelial cells (HUVECs) was performed by treating with lipopolysaccharide (LPS) or hypoxia/reoxygenation. We assessed CMTM3 expression levels in the LPS- and hypoxia/reoxygenation-stimulated HUVEC cells. Furthermore, we assessed the role of CMTM3 in the permeability function and inflammatory response of the vascular endothelial cells under ARDS conditions using HUVEC cells with CMTM3 overexpression(adCMTM3) or knockdown(shCMTM3). Concurrently, we generated CMTM3 knockout (CMTM3ko) mice and evaluated the differences in pulmonary vascular permeability, inflammatory lung injury, and survival rates between the CMTM3ko-ARDS and WT-ARDS model mice. Results HUVECs stimulated with LPS and hypoxia/reoxygenation showed significantly higher CMTM3 expression compared to the control group (p<0.05). Compared with the adsham-HUVECs, adCMTM3-HUVECs stimulated with LPS and hypoxia/reoxygenation demonstrated significantly higher cellular permeability (p<0.05) as well as IL-6 and TNF-α expression levels (p<0.05). Conversely, shCMTM3-HUVECs stimulated with LPS and hypoxia/reoxygenation showed significantly reduced cellular permeability as well as IL-6 and TNF-α expression levels (p<0.05). In vivo ARDS modeling experiments demonstrated that CMTM3-knockout ARDS mice exhibited significantly higher survival rates (p=0.0194) as well as significantly reduced lung injury and pulmonary vascular permeability (p<0.05) compared to the wild-type ARDS mice. Discussion These findings demonstrated that CMTM3 played a critical role in the development of ARDS by influencing permeability of the pulmonary vascular endothelial cells and lung inflammation. Therefore, CMTM3 is a potential therapeutic target in ARDS.
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Affiliation(s)
- Ziyan Xiao
- Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China
- National Center for Trauma Medicine of China, Peking University People's Hospital, Beijing, China
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Peking University People’s Hospital, Beijing, China
| | - Gang Zhou
- Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China
- National Center for Trauma Medicine of China, Peking University People's Hospital, Beijing, China
| | - Haiyan Xue
- Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China
- National Center for Trauma Medicine of China, Peking University People's Hospital, Beijing, China
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Peking University People’s Hospital, Beijing, China
| | - Lihe Chen
- Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China
- National Center for Trauma Medicine of China, Peking University People's Hospital, Beijing, China
- Beijing Key Surgical Basic Research Laboratory of Liver Cirrhosis and Liver Cancer, Peking University People’s Hospital, Beijing, China
| | - Xiujuan Zhao
- Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China
| | - Shu Li
- Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China
- National Center for Trauma Medicine of China, Peking University People's Hospital, Beijing, China
| | - Chun Fu
- Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China
- National Center for Trauma Medicine of China, Peking University People's Hospital, Beijing, China
| | - Zhengzhou Wang
- Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China
- National Center for Trauma Medicine of China, Peking University People's Hospital, Beijing, China
| | - Fengxue Zhu
- Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China
- National Center for Trauma Medicine of China, Peking University People's Hospital, Beijing, China
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Ulaş N, Üstündağ H, Özkanlar S, Erbaş E, Kara A, Özkanlar Y. D-carvone attenuates LPS-induced acute lung injury via TLR4/NF-κB and Nrf2/HO-1 signaling pathways in rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04024-y. [PMID: 40116872 DOI: 10.1007/s00210-025-04024-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 03/05/2025] [Indexed: 03/23/2025]
Abstract
Acute lung injury (ALI) is a severe respiratory disorder associated with high morbidity and mortality. Lipopolysaccharide (LPS) is widely used to induce ALI in animal models. D-carvone, a natural monoterpene, has been reported to possess anti-inflammatory and antioxidant properties. This study aimed to investigate the protective effects of D-carvone on LPS-induced ALI in rats. Thirty-six male rats were randomly divided into six groups (n = 6): control, D-carvone (10 mg/kg and 20 mg/kg p.o.), LPS (10 mg/kg E. coli lipopolysaccharide i.p.), and LPS + D-carvone (LPS with either 10 or 20 mg/kg D-carvone). D-carvone was administered orally once daily for 10 days. On day 10, sepsis was induced with LPS administration, and samples were collected after 6 h under deep anesthesia. LPS administration caused significant lung injury, as evidenced by increased histopathological scores, upregulation of pro-inflammatory markers (TLR4, IL-1β, TNF-α), and oxidative stress (increased MDA, decreased GSH and SOD). Treatment with D-carvone at both doses significantly attenuated these changes. D-carvone downregulated pro-inflammatory markers, upregulated anti-inflammatory (NRF2) and anti-apoptotic (Bcl-2) proteins, and reduced the levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8) in lung tissues. In conclusion, D-carvone protects against LPS-induced ALI in rats, possibly through its anti-inflammatory and antioxidant properties. These findings suggest that D-carvone could be a potential therapeutic candidate for preventing and treating ALI.
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Affiliation(s)
- Nergis Ulaş
- Department of Internal Medicine, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey
| | - Hilal Üstündağ
- Department of Physiology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey.
| | - Seçkin Özkanlar
- Department of Biochemistry, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey
| | - Elif Erbaş
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Adem Kara
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey
| | - Yunusemre Özkanlar
- Department of Internal Medicine, Faculty of Veterinary, Ondokuz Mayis University, Samsun, Turkey
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Tian X, Lu B, Huang Y, Zhong W, Lei X, Liu S, Tao T, Yun F, Huang S, Tan T, Liu H, Zhou Z, Peng G, Wang Y, Zhang K, Luo X, Zhong Z. Associated effects of lipopolysaccharide, oleic acid, and lung injury ventilator-induced in developing a model of moderate acute respiratory distress syndrome in New Zealand white rabbits. Front Vet Sci 2025; 12:1477554. [PMID: 40177676 PMCID: PMC11963770 DOI: 10.3389/fvets.2025.1477554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 03/03/2025] [Indexed: 04/05/2025] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a critical pulmonary disorder with manifestations of pulmonary edema, inflammation, and impaired oxygenation. Establishing reliable animal ARDS models has been critical for investigating its mechanisms and for testing pharmacological interventions. The present study sought to induce a moderate ARDS model in New Zealand White rabbits with a model involving a mix of lipopolysaccharide (LPS), oleic acid (OA), and ventilation-induced lung injury (VILI). Four experimental groups were established: negative control (NC, n = 4), OA (OM, n = 6), LPS + OA (LOM, n = 6), and LPS + OA + VILI (LOV, n = 6). Throughout the modeling process, vital signs (MAP and HR), respiratory parameters (Cdyn), and hematological indices (WBC and P/F) were continuously monitored, and lung ultrasound was performed. After the experiment, bronchoalveolar lavage fluid (BALF) was collected to measure total protein content, and lung tissue samples were collected to determine the wet-to-dry (W/D) ratio. HE-stained lung tissue sections were prepared and scored according to the ATS guidelines for lung injury scoring. The LOV group showed the most severe lung injury, significantly decreasing MAP and Cdyn. Pathological and ultrasound scores were considerably higher in the LOV group compared to the OM and LOM groups (p < 0.05). The lung W/D ratio was significantly higher in the LOM (6.68 ± 0.56) and LOV (7.40 ± 0.56) groups compared to the NC group (5.20 ± 0.16) (p < 0.05). At T6, the PaO2/FiO2 ratio in the LOV group was ≤200 mmHg, significantly lower than that in the NC group (p < 0.05). Some rabbits in the OM and LOM groups also had PaO2/FiO2 ratios ≤200 mmHg, but the difference compared to the NC group was not statistically significant. In conclusion, this study established a novel moderate ARDS model in New Zealand White rabbits using LPS, OA, and VILI. The model demonstrates severe lung damage, pulmonary edema, and sustained hypoxemia, providing a basis for future research.
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Affiliation(s)
- Xingyu Tian
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Bin Lu
- Department of Pediatric Critical Medicine, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuyan Huang
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Wenhao Zhong
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xin Lei
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Siyu Liu
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Tao Tao
- Department of Pediatric Critical Medicine, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Fengning Yun
- Department of Pediatric Critical Medicine, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shiyong Huang
- Department of Pediatric Critical Medicine, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Tiqing Tan
- Department of Pediatric Critical Medicine, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Haifeng Liu
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ziyao Zhou
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Guangneng Peng
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ya Wang
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Kun Zhang
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xiaoli Luo
- Department of Pediatric Critical Medicine, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhijun Zhong
- Key Laboratory of Animal Disease and Human Health of Sichuan, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
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Moustafa HAM, Elbery FH, Al Meslamani AZ, Okda SM, Alsfouk BA, Kassem AB. Evaluating the Use of Inhaled Budesonide and Ipratropium Bromide Combination in Patients at High Risk of Acute Respiratory Distress Syndrome Development: A Randomized Controlled Trial. Pharmaceuticals (Basel) 2025; 18:412. [PMID: 40143188 PMCID: PMC11945358 DOI: 10.3390/ph18030412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/08/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Objectives: There is a scarcity of pharmacological treatments that efficiently address lung injury in individuals experiencing acute respiratory distress syndrome (ARDS). Early inhaled corticosteroids and ipratropium may reduce pulmonary inflammation and injury of the lungs, minimizing the risk of ARDS. Method: This is a double-blinded randomized control trial conducted on patients at risk of ARDS. Patients were randomly allocated into two groups; the intervention group (63 patients) were administered aerosolized budesonide and ipratropium bromide, and the control group (56) were administered a placebo every eight hours for five days. Alteration in oxygen saturation divided by inspired oxygen (Fio2) (S/F) after five days was the primary outcome. Secondary outcomes included ARDS occurrence, mechanical ventilation (MV) requirement, hospital stay duration, and mortality rates. Results: Of the 604 screened, only 119 patients were included. The intervention group (63 patients) S/F ratio recovered versus the fall of the control group. Both groups had similar organ dysfunction and 28-day mortality. The intervention group had significantly (p < 0.001) fewer cases developing ARDS (9.5%) and MV (9.5%) than the control group (46.4% and 35.7%, respectively). Conclusions: The administration of inhaled budesonide and ipratropium bromide improved oxygenation, as assessed by the S/F ratio, and significantly reduced the rate of ARDS development and the requirement of MV versus the control group. Larger multi-center trials including diverse patient populations are needed to validate these results.
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Affiliation(s)
| | - Faten H. Elbery
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al Salam University, Kafr Alzayat 31611, Algharbia, Egypt;
| | - Ahmad Z. Al Meslamani
- College of Pharmacy, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirates;
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi P.O. Box 112612, United Arab Emirate
| | - Sherouk M. Okda
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Damanhour University, Damanhour 22514, Egypt;
| | - Bshra A. Alsfouk
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia;
| | - Amira B. Kassem
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Damanhour University, Damanhour 22514, Egypt;
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Fosset M, von Wedel D, Redaelli S, Talmor D, Molinari N, Josse J, Baedorf-Kassis EN, Schaefer MS, Jung B. Subphenotyping prone position responders with machine learning. Crit Care 2025; 29:116. [PMID: 40087660 PMCID: PMC11909901 DOI: 10.1186/s13054-025-05340-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/25/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is a heterogeneous condition with varying response to prone positioning. We aimed to identify subphenotypes of ARDS patients undergoing prone positioning using machine learning and assess their association with mortality and response to prone positioning. METHODS In this retrospective observational study, we enrolled 353 mechanically ventilated ARDS patients who underwent at least one prone positioning cycle. Unsupervised machine learning was used to identify subphenotypes based on respiratory mechanics, oxygenation parameters, and demographic variables collected in supine position. The primary outcome was 28-day mortality. Secondary outcomes included response to prone positioning in terms of respiratory system compliance, driving pressure, PaO2/FiO2 ratio, ventilatory ratio, and mechanical power. RESULTS Three distinct subphenotypes were identified. Cluster 1 (22.9% of whole cohort) had a higher PaO2/FiO2 ratio and lower Positive End-Expiratory Pressure (PEEP). Cluster 2 (51.3%) had a higher proportion of COVID-19 patients, lower driving pressure, higher PEEP, and higher respiratory system compliance. Cluster 3 (25.8%) had a lower pH, higher PaCO2, and higher ventilatory ratio. Mortality differed significantly across clusters (p = 0.03), with Cluster 3 having the highest mortality (56%). There were no significant differences in the proportions of responders to prone positioning for any of the studied parameters. Transpulmonary pressure measurements in a subcohort did not improve subphenotype characterization. CONCLUSIONS Distinct ARDS subphenotypes with varying mortality were identified in patients undergoing prone positioning; however, predicting which patients benefited from this intervention based on available data was not possible. These findings underscore the need for continued efforts in phenotyping ARDS through multimodal data to better understand the heterogeneity of this population.
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Affiliation(s)
- Maxime Fosset
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Center for Anesthesia Research Excellence (CARE), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Medical Intensive Care Unit and PhyMedExp, Lapeyronie Montpellier University Hospital, Lapeyronie Teaching Hospital, University Montpellier, 1; 371 Avenue Du Doyen Gaston Giraud, 34090, Montpellier, CEDEX 5, France
- Desbrest Institute of Epidemiology and Public Health, University of Montpellier, INRIA, Montpellier, France
| | - Dario von Wedel
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Center for Anesthesia Research Excellence (CARE), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Institute of Medical Informatics, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Simone Redaelli
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Center for Anesthesia Research Excellence (CARE), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Department of Anesthesiology, Perioperative and Pain Medicine, Lahey Hospital and Medical Center, Burlington, MA, USA
| | - Daniel Talmor
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Center for Anesthesia Research Excellence (CARE), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Nicolas Molinari
- Desbrest Institute of Epidemiology and Public Health, University of Montpellier, INRIA, Montpellier, France
| | - Julie Josse
- Desbrest Institute of Epidemiology and Public Health, University of Montpellier, INRIA, Montpellier, France
| | - Elias N Baedorf-Kassis
- Department of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Maximilian S Schaefer
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Center for Anesthesia Research Excellence (CARE), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Department of Anesthesiology, Duesseldorf University Hospital, Duesseldorf, Germany
| | - Boris Jung
- Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- Center for Anesthesia Research Excellence (CARE), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
- Medical Intensive Care Unit and PhyMedExp, Lapeyronie Montpellier University Hospital, Lapeyronie Teaching Hospital, University Montpellier, 1; 371 Avenue Du Doyen Gaston Giraud, 34090, Montpellier, CEDEX 5, France.
- Department of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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Gaver DP, Kollisch-Singule M, Nieman G, Satalin J, Habashi N, Bates JHT. Mechanical ventilation energy analysis: Recruitment focuses injurious power in the ventilated lung. Proc Natl Acad Sci U S A 2025; 122:e2419374122. [PMID: 40030025 PMCID: PMC11912383 DOI: 10.1073/pnas.2419374122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 01/22/2025] [Indexed: 03/19/2025] Open
Abstract
The progression of acute respiratory distress syndrome (ARDS) from its onset due to disease or trauma to either recovery or death is poorly understood. Currently, there are no generally accepted treatments aside from supportive care using mechanical ventilation. However, this can lead to ventilator-induced lung injury (VILI), which contributes to a 30 to 40% mortality rate. In this study, we develop and demonstrate a technique to quantify forms of energy transport and dissipation during mechanical ventilation to directly evaluate their relationship to VILI. A porcine ARDS model was used, with ventilation parameters independently controlling lung overdistension and alveolar/airway recruitment/derecruitment (RD). Hourly measurements of airflow, tracheal and esophageal pressures, respiratory system impedance, and oxygen transport were taken for six hours following lung injury to track energy transfer and lung function. The final degree of injury was assessed histologically. Total and dissipated energies were quantified from lung pressure-volume relationships and subdivided into contributions from airflow, tissue viscoelasticity, and RD. Only RD correlated with physiologic recovery. Despite accounting for a very small fraction (2 to 5%) of the total energy dissipation, RD is damaging because it occurs quickly over a very small area. We estimate power intensity of RD energy dissipation to be 100 W/m2, equivalent to 10% of the Sun's luminance at the Earth's surface. Minimizing repetitive RD events may thus be crucial for mitigating VILI.
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Affiliation(s)
- Donald P. Gaver
- Department of Biomedical Engineering, Tulane University, New Orleans, LA70118
| | | | - Gary Nieman
- Department of Surgery, State University of New York Upstate Medical University, Syracuse, NY13210
| | - Joshua Satalin
- Department of Surgery, State University of New York Upstate Medical University, Syracuse, NY13210
| | - Nader Habashi
- Department of Trauma Critical Care Medicine, R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD21201
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Shen YZ, Yao YD, Li HL, Li Y, Hu YC. CTSO and HLA-DQA1 as biomarkers in sepsis-associated ARDS: insights from RNA sequencing and immune infiltration analysis. BMC Infect Dis 2025; 25:326. [PMID: 40055592 PMCID: PMC11887161 DOI: 10.1186/s12879-025-10726-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 02/27/2025] [Indexed: 05/13/2025] Open
Abstract
The onset of sepsis frequently coincides with acute respiratory distress syndrome (ARDS), which constitutes a significant contributor to severe acid-base disturbances in septic patients. In the pathogenesis of sepsis, it conducts a crucial role. lysosomal metabolic disorders and immune imbalance conduct a pivotal role. Despite extensive research into the alterations in immune status during sepsis, few studies have been reported to thoroughly examine the association between lysosomes and sepsis. As a result, this study is predominantly Intended to delve into the link between lysosome-related genes and alterations in the lysosome in the immune microenvironment from the standpoint of bioinformatics in sepsis. The Registration Number was ChiCTR1900021261. Registration Date is 2019/02/04. Method Sepsis data source: Sepsis data was collected from previous clinical data and sequencing results (Originated from BGI Shenzhen Co., Ltd.) and the GO database was utilized for data collection of lysosome-related genes. Differential expression genes (DEGs) were screened on clinical sequencing data by employing IDEP 0.93 software subsequent to quality control. Afterwards, enrichment analysis was conducted by adopting Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co expression Network Analysis (WGCNA), followed by cross referencing of lysosomal genes to identify DEGs associated with lysosomes. GO and KEGG pathway analysis wereperformed subsequently. The genes obtained from PLSGs and WGCNA by Creating a PPI network entails the following steps: the points were intersected at first. Afterwards, CytoHubba and MCODE analysis were performed by utilizing cytoscape software. Next, the intersection was taken to confirm Hub gene sequences, and subsequently the central DEGs tightly associated with existing CTD scores. Notwithstanding the fact that the causes of sepsis are multifaceted, ARDS can often trigger the development of sepsis in numerous cases. Simultaneously, with an aim to predict transcription factor levels in the central nervous system, Cytoscape software was adopted DEGs and to find relevant target miRNAs in the miRWalk database, and a correlated regulatory network was established accordingly. The SEPSIS immune infiltration model was constructed by employing ImmuCellAI software. Afterwards, the association between DEGs and immune microenvironment abundance was constructed by adopting Spearman's method. Last but not least, it is worth noting that single-cell sequencing has been validated as a method to analyze hub gene expression in immune cells of sepsis patients, enabling the selection of key genes that are closely associated with predictive outcomes. Result When acute respiratory distress syndrome (ARDS) is present, the differentially expressed genes (DEGs) are implicated in lysosomal metabolism and the regulation of the immune microenvironment. Six hub DEGs were bound up with sepsis or was attributable to the examinations. On top of that, it was determined that the patients had acute respiratory distress syndrome. The associated immune analysis illustrated a remarkable augment in T cell infiltration in the immune microenvironment of sepsis, while the infiltration relative to DC was reduced at certain level. Positive correlations were found between the two by employing Spearman analysis between hub DEGs and the regulatory role of immune cells. Moreover, it was universally acknowledged that anti-inflammatory immune cells were responsible for the negative correlation. On the basis of single-cell sequencing, it has been determined that CTSO and HLA-DQA1 were expressed in immune cells in sepsis. Aside from that, the survival-death curve direction suggested that they could be utilized as core genes for predicting sepsis-related prognosis analysis. Conclusion An analysis of this study demonstrates the interaction between sepsis lysosome-related metabolism and changes by understanding the pathogenesis of immune cells in the microenvironment. On this basis, we can develop new clinical diagnostics and therapeutic approaches of sepsis and identifying drug targets. Nonetheless, ARDS and sepsis can differ simply by the difference in site of infection; as the etiology of numerous ARDS cases is quite complex, progression to sepsis can occur if infection exacerbates or other complications arise, meeting the diagnostic criteria of sepsis 3.0.
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Affiliation(s)
- Yu Zhou Shen
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, Lu Zhou, People's Republic of China
| | - Yan Dong Yao
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, Lu Zhou, People's Republic of China
| | - Hai Li Li
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, Lu Zhou, People's Republic of China
| | - Yang Li
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, Lu Zhou, People's Republic of China
| | - Ying Chun Hu
- Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, Lu Zhou, People's Republic of China.
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Wang Y, Zhang LF, Zhang JJ, Yu SS, Li WL, Zhou TJ, Xing L, Jeong JH, Jiang HL. Spontaneous Inflammation Resolution Inspired Nanoparticles Promote Neutrophil Apoptosis and Macrophage Efferocytosis for Acute Respiratory Distress Syndrome Treatment. Adv Healthc Mater 2025; 14:e2402421. [PMID: 39723664 DOI: 10.1002/adhm.202402421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 12/16/2024] [Indexed: 12/28/2024]
Abstract
During acute respiratory distress syndrome (ARDS), delayed apoptosis of neutrophils and impaired efferocytosis of macrophages constitute two critical limiting steps, leading to secondary inflammatory storm and posing a significant threat to human health. However, due to the failure of previous single target-centric treatments to effectively address these two limiting steps in controlling the inflammatory storm, no available therapies are approved for ARDS treatment. Herein, inspired by spontaneous inflammation resolution, two kinds of Apoptosis and Efferocytosis Restored Nanoparticles (AER NPs) are proposed to overcome these two limiting steps for counteracting severe inflammatory storm. For the first limiting step, neutrophil-targeted apoptosis-restored nanoparticles (AR NPs) accelerated the programmed apoptosis of inflammatory neutrophils. The resolution of the first limiting step facilitated the accumulation of macrophage-targeted and efferocytosis-restored nanoparticles (ER NPs), thereby restoring macrophage efferocytosis and alleviating the second limiting step. The results indicated that after sequential treatment with AER NPs, recruited neutrophils decreased to 13.86%, and macrophage efferocytosis increased to 563.24%. AER NPs promoted inflammation resolution and established a self-healing virtuous loop by addressing the two limiting steps, ultimately effectively treating ARDS. This work suggests that a strategy inspired by inflammation resolution holds promise as a potential approach for advancing inflammation therapy.
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Affiliation(s)
- Yi Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China
| | - Ling-Feng Zhang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China
| | - Jiao-Jiao Zhang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China
| | - Si-Si Yu
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China
| | - Wen-Ling Li
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China
| | - Tian-Jiao Zhou
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, South Korea
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, South Korea
- College of Pharmacy, Yanbian University, Yanji, 133002, China
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Mady AF, Hamido HM, Abdulrahman B, Mady AA, Aletreby AW, Abdalla AA, Gano JQ, Hashim Aletreby WT. Effect of Nebulized Furosemide on the Mortality of Adult, Mechanically Ventilated Acute Respiratory Distress Syndrome (ARDS) Patients: Protocol of a Randomized Clinical Trial (The ENHALE Trial). Cureus 2025; 17:e81006. [PMID: 40260371 PMCID: PMC12011351 DOI: 10.7759/cureus.81006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2025] [Indexed: 04/23/2025] Open
Abstract
Background Acute respiratory distress syndrome (ARDS) affects a significant proportion of ICU patients and has a high mortality rate. The inflammation of the alveolar-capillary membrane is pathognomonic and characterized by increased capillary permeability and pulmonary edema. A safe, readily available anti-inflammatory agent delivered directly to the lungs could be a promising therapeutic approach. All these properties apply to nebulized furosemide. Objectives The primary objective of this study is to analyze 28-day all-cause ICU mortality while the secondary objectives include assessing hospital mortality, ICU and hospital length of stay (LOS), ventilator-free days at 28 days, successful extubation rate, and adverse events. Methods A double-blind, placebo-controlled, parallel-arm superiority RCT using an intention-to-treat (ITT) analysis to assess whether nebulized furosemide reduces mortality in adult mechanically ventilated ARDS patients will be employed. Results The results of descriptive and inferential analyses will be tabulated, and the significant results will be presented.
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Affiliation(s)
- Ahmed F Mady
- Anesthesiology and Intensive Care, Tanta University Hospitals, Tanta, EGY
- Critical Care Medicine, King Saud Medical City, Riyadh, SAU
| | - Hend M Hamido
- Critical Care Medicine, King Saud Medical City, Riyadh, SAU
| | | | - Anas A Mady
- College of Medicine, Alfaisal University College of Medicine, Riyadh, SAU
| | | | - Ahmed A Abdalla
- College of Medicine, Alfaisal University College of Medicine, Riyadh, SAU
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Meza-Fuentes G, Delgado I, Barbé M, Sánchez-Barraza I, Retamal MA, López R. Machine learning-based identification of efficient and restrictive physiological subphenotypes in acute respiratory distress syndrome. Intensive Care Med Exp 2025; 13:29. [PMID: 40024962 PMCID: PMC11872963 DOI: 10.1186/s40635-025-00737-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 02/14/2025] [Indexed: 03/04/2025] Open
Abstract
INTRODUCTION Acute respiratory distress syndrome (ARDS) is a severe condition with high morbidity and mortality, characterized by significant clinical heterogeneity. This heterogeneity complicates treatment selection and patient inclusion in clinical trials. Therefore, the objective of this study is to identify physiological subphenotypes of ARDS using machine learning, and to determine ventilatory variables that can effectively discriminate between these subphenotypes in a bedside setting with high performance, highlighting potential utility for future clinical stratification approaches. METHODOLOGY A retrospective cohort study was conducted using data from our ICU, covering admissions from 2017 to 2021. The study included 224 patients over 18 years of age diagnosed with ARDS according to the Berlin criteria and undergoing invasive mechanical ventilation (IMV). Data on physiological and ventilatory variables were collected during the first 24 h IMV. We applied machine learning techniques to categorize subphenotypes in ARDS patients. Initially, we employed the unsupervised Gaussian Mixture Classification Model approach to group patients into subphenotypes. Subsequently, we applied supervised models such as XGBoost to perform root cause analysis, evaluate the classification of patients into these subgroups, and measure their performance. RESULTS Our models identified two ARDS subphenotypes with significant clinical differences and significant outcomes. Subphenotype Efficient (n = 172) was characterized by lower mortality, lower clinical severity and presented a less restrictive pattern with better gas exchange compared to Subphenotype Restrictive (n = 52), which showed the opposite. The models demonstrated high performance with an area under the ROC curve of 0.94, sensitivity of 94.2% and specificity of 87.5%, in addition to an F1 score of 0.85. The most influential variables in the discrimination of subphenotypes were distension pressure, respiratory frequency and exhaled carbon dioxide volume. CONCLUSION This study presents an approach to improve subphenotype categorization in ARDS. The generation of clustering and prediction models by machine learning involving clinical, ventilatory mechanics, and gas exchange variables allowed for more accurate stratification of patients. These findings have the potential to optimize individualized treatment selection and improve clinical outcomes in patients with ARDS.
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Affiliation(s)
- Gabriela Meza-Fuentes
- Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile
| | - Iris Delgado
- Centro de Epidemiología y Políticas de Salud, Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile
| | - Mario Barbé
- Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile
| | - Ignacio Sánchez-Barraza
- Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile
| | - Mauricio A Retamal
- Programa de Comunicación Celular en Cáncer, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile
| | - René López
- Grupo Intensivo, ICIM, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
- Departamento de Paciente Crítico, Clínica Alemana de Santiago, Santiago, Chile.
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Magloire C, Aghabekyan T, Morley NE, Turcan S, Sexton S, Khatoon D, Okoye C, McFarlane SI. Severe Acute Respiratory Distress Syndrome in Lyme Disease: A Case Report and Review of the Literature. Cureus 2025; 17:e81170. [PMID: 40276406 PMCID: PMC12021006 DOI: 10.7759/cureus.81170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Accepted: 03/25/2025] [Indexed: 04/26/2025] Open
Abstract
While there are many etiologies of acute respiratory distress syndrome (ARDS), Lyme disease is not a known cause of this disorder, and there is a paucity of Lyme-associated ARDS cases reported in the medical literature. In this report, we present a case of a 70-year-old woman with ARDS requiring mechanical ventilation, who initially had recurrent negative infectious workups but was ultimately diagnosed with Lyme disease with positive Lyme serology and western blot. The patient, who is from the New York City metropolitan area, had no outdoor exposure, recent travel history, or sick contacts. She experienced a complicated intensive care unit (ICU) course, including septic shock requiring antibiotics, vasopressors, and multiple diagnostic tests. Ultimately, the patient recovered and was transferred to the medicine unit and subsequently discharged in stable condition. This case highlights a rare complication of Lyme disease and highlights the importance of considering rare etiologies in the differential diagnosis of ARDS with an unclear etiology.
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Affiliation(s)
- Chris Magloire
- Internal Medicine, State University of New York Downstate Health Sciences University, New York, USA
| | - Tigran Aghabekyan
- Internal Medicine, State University of New York Downstate Health Sciences University, New York, USA
| | - Nicholas E Morley
- Internal Medicine, State University of New York Downstate Medical Center, New York, USA
| | - Sava Turcan
- Anesthesiology, State University of New York Downstate Health Sciences University, New York, USA
| | - Shawn Sexton
- Anesthesiology, State University of New York Downstate Medical Center, New York, USA
| | - Dilruba Khatoon
- Anesthesiology, State University of New York Downstate Health Sciences University, New York, USA
| | - Chibuzo Okoye
- Critical Care Medicine, State University of New York Downstate Health Sciences University, New York, USA
| | - Samy I McFarlane
- Internal Medicine, State University of New York Downstate Health Sciences University, New York, USA
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Watabe Y, Giam Chuang VT, Sakai H, Ito C, Enoki Y, Kohno M, Otagiri M, Matsumoto K, Taguchi K. Carbon monoxide alleviates endotoxin-induced acute lung injury via NADPH oxidase inhibition in macrophages and neutrophils. Biochem Pharmacol 2025; 233:116782. [PMID: 39880317 DOI: 10.1016/j.bcp.2025.116782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 01/17/2025] [Accepted: 01/25/2025] [Indexed: 01/31/2025]
Abstract
Sepsis is a life-threatening condition caused by severe infection and often complicates acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) due to the collapse of the oxidative and inflammatory balance induced by microbial pathogens, including lipopolysaccharides (LPS). In sepsis-related ARDS/ALI, NADPH oxidase (NOX) and toll-like receptors (TLR) in neutrophils and macrophages are key players in initiating oxidative and inflammatory imbalances. Although NOX and TLR activation has been linked to carbon monoxide (CO), the mechanism by which CO affects sepsis-related ARDS/ALI through NOX and TLR remains unknown. Here, we demonstrate that CO reduces sepsis-related ARDS/ALI by inhibiting NOX in neutrophils and macrophages, which in turn suppresses the production of reactive oxygen species (ROS), TLR4-associated inflammatory responses, and macrophage polarization toward M1-like macrophages. CO-bound hemoglobin vesicle (CO-HbV) therapy, a hemoglobin-based CO donor, exerts a protective effect against LPS-induced ALI by suppressing exaggerated oxidative and inflammatory responses and neutrophil and M1-like macrophage infiltration in the bronchoalveolar lavage fluid (BALF). Through suppression of NOX activity, CO decreased ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization toward M1-like macrophages, according to cellular experiments conducted with peripheral neutrophils, BALF cells, and Raw264.7 cells. Moreover, ALI was found to be more severe in Hmox1+/- mice (mice with decreased endogenous CO production) than in the wild-type mice. Our findings suggest that both endogenously generated and exogenously supplied CO inhibit NOX-associated ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization, thereby eliciting antioxidant and anti-inflammatory responses that prevent the onset and progression of LPS-induced ALI.
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Affiliation(s)
- Yuki Watabe
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Victor Tuan Giam Chuang
- Discipline of Pharmacy, Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, Australia
| | - Hiromi Sakai
- Department of Chemistry, Nara Medical University, Nara, Japan
| | - Chihiro Ito
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Yuki Enoki
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Mitsutomo Kohno
- Department of General Thoracic Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences and DDS Research Institute, Sojo University, Kumamoto, Japan
| | - Kazuaki Matsumoto
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Kazuaki Taguchi
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
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Morita Y, Kariya T, Torjman M, Pfeil D, Berg K, Vetrugno L, Raphael J, Goldhammer J. Comparison of Manual and Mechanical Ventilation During Intensive Care Unit Transport Following Cardiac Surgery: Impact on Oxygenation, Ventilation, and Hemodynamic Stability. J Cardiothorac Vasc Anesth 2025; 39:644-652. [PMID: 39757025 DOI: 10.1053/j.jvca.2024.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/07/2024] [Accepted: 12/11/2024] [Indexed: 01/07/2025]
Abstract
OBJECTIVES Following cardiac surgery, patients often require ventilatory support during transport to the intensive care unit (ICU). Manual ventilation using a bag valve mask (BVM) is commonly employed; however, mechanical ventilation may sometimes be preferred due to concerns regarding oxygenation, ventilation, and hemodynamic stability. The decision between manual and mechanical ventilation is typically based on clinical experience and surgical factors, as there is no established consensus or robust clinical evidence to guide this choice. The aim of this study was to compare oxygenation, ventilation, and hemodynamic parameters between manual ventilation with a BVM and mechanical ventilation using a transport ventilator. DESIGN A prospective, single-blinded clinical trial. SETTING A single-center tertiary academic hospital. PARTICIPANTS A total of 48 patients who underwent cardiac surgery and were transported to the ICU between September 2023 and August 2024 were enrolled. INTERVENTIONS Patients meeting the inclusion criteria were randomly assigned to one of two groups: Patients in Arm 1received manual ventilation using a BVM during transport to the ICU; patients in Arm 2 received mechanical ventilation using a transport ventilator during transport to the ICU. MEASUREMENTS AND MAIN RESULTS Percentage changes in the PaO2/FiO2 ratio and PaCO2 pre- and post-transport were not significantly different between the two groups (p = 0.133 and 0.902, respectively). However, hypotension, defined as a >10% decrease in mean arterial pressure, was significantly more frequent in the BVM group than in the mechanical ventilation group (p = 0.00986). CONCLUSIONS In patients who have undergone cardiac surgery, hypotension occurred more frequently in the BVM group than in the mechanical ventilation group during transport to the ICU. However, oxygenation and ventilation parameters were comparable between the two groups.
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Affiliation(s)
- Yoshihisa Morita
- Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA.
| | - Taro Kariya
- Department of Anesthesiology, University of Tokyo, Tokyo, Japan
| | - Marc Torjman
- Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA
| | - Doug Pfeil
- Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA
| | - Kent Berg
- Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA
| | - Luigi Vetrugno
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Chieti, Italy
| | - Jacob Raphael
- Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA
| | - Jordan Goldhammer
- Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA
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Zheng Z, Qiao X, Yin J, Kong J, Han W, Qin J, Meng F, Tian G, Feng X. Advancements in omics technologies: Molecular mechanisms of acute lung injury and acute respiratory distress syndrome (Review). Int J Mol Med 2025; 55:38. [PMID: 39749711 PMCID: PMC11722059 DOI: 10.3892/ijmm.2024.5479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 12/09/2024] [Indexed: 01/04/2025] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory response arising from lung and systemic injury with diverse causes and associated with high rates of morbidity and mortality. To date, no fully effective pharmacological therapies have been established and the relevant underlying mechanisms warrant elucidation, which may be facilitated by multi‑omics technology. The present review summarizes the application of multi‑omics technology in identifying novel diagnostic markers and therapeutic strategies of ALI/ARDS as well as its pathogenesis.
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Affiliation(s)
- Zhihuan Zheng
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
- Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Xinyu Qiao
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
- Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Junhao Yin
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
- Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Junjie Kong
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
- Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Wanqing Han
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
- Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Jing Qin
- Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Fanda Meng
- Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Ge Tian
- School of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong 271000, P.R. China
| | - Xiujing Feng
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
- Department of Immunology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
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Mekontso Dessap A, AlShamsi F, Belletti A, De Backer D, Delaney A, Møller MH, Gendreau S, Hernandez G, Machado FR, Mer M, Monge Garcia MI, Myatra SN, Peng Z, Perner A, Pinsky MR, Sharif S, Teboul JL, Vieillard-Baron A, Alhazzani W. European Society of Intensive Care Medicine (ESICM) 2025 clinical practice guideline on fluid therapy in adult critically ill patients: part 2-the volume of resuscitation fluids. Intensive Care Med 2025; 51:461-477. [PMID: 40163133 DOI: 10.1007/s00134-025-07840-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 02/11/2025] [Indexed: 04/02/2025]
Abstract
OBJECTIVE This European Society of Intensive Care Medicine (ESICM) guideline provides evidence-based recommendations on the volume of early resuscitation fluid for adult critically ill patients. METHODS An international panel of experts developed the guideline, focusing on fluid resuscitation volume in adult critically ill patients with circulatory failure. Using the PICO format, questions were formulated, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was applied to assess evidence and formulate recommendations. RESULTS In adults with sepsis or septic shock, the guideline suggests administering up to 30 ml/kg of intravenous crystalloids in the initial phase, with adjustments based on clinical context and frequent reassessments (very low certainty of evidence). We suggest using an individualized approach in the optimization phase (very low certainty of evidence). No recommendation could be made for or against restrictive or liberal fluid strategies in the optimization phase (moderate certainty of no effect). For hemorrhagic shock, a restrictive fluid strategy is suggested after blunt trauma (moderate certainty) and penetrating trauma (low certainty), with fluid administration for non-traumatic hemorrhagic shock guided by hemodynamic and biochemical parameters (ungraded best practice). For circulatory failure due to left-sided cardiogenic shock, fluid resuscitation as the primary treatment is not recommended. Fluids should be administered cautiously for cardiac tamponade until definitive treatment and guided by surrogate markers of right heart congestion in acute pulmonary embolism (ungraded best practice). No recommendation could be made for circulatory failure associated with acute respiratory distress syndrome. CONCLUSIONS The panel made four conditional recommendations and four ungraded best practice statements. No recommendations were made for two questions. Knowledge gaps were identified, and suggestions for future research were provided.
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Affiliation(s)
- Armand Mekontso Dessap
- Medical Intensive Care, Henri-Mondor Hospital (AP-HP), UPEC, IMRB, CARMAS Research Group, Creteil, France.
- CARMAS research group, IMRB, UPEC, Créteil, France.
| | - Fayez AlShamsi
- Department of Internal Medicine, College of Medicine and Health Sciences, Emirates University, Al Ain, United Arab Emirates
| | - Alessandro Belletti
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Daniel De Backer
- Department of Intensive Care, CHIREC Hospitals, Université Libre de Bruxelles, Brussels, Belgium
| | - Anthony Delaney
- Critical Care Program, The George Institute for Global Health, Sydney, NSW, Australia
| | - Morten Hylander Møller
- Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Segolène Gendreau
- Medical Intensive Care, Henri-Mondor Hospital (AP-HP), UPEC, IMRB, CARMAS Research Group, Creteil, France
- CARMAS research group, IMRB, UPEC, Créteil, France
| | - Glenn Hernandez
- Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Flavia R Machado
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Mervyn Mer
- Department of Medicine, Divisions of Critical Care and Pulmonology, Faculty of Health Sciences, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa
| | | | - Sheila Nainan Myatra
- Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Zhiyong Peng
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Anders Perner
- Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet and Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Michael R Pinsky
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA
| | - Sameer Sharif
- Division of Critical Care and Emergency Medicine, Department of Medicine, McMaster University, Hamilton, Canada
| | - Jean-Louis Teboul
- Medical Intensive Care, Bicetre Hospital (AP-HP), Le Kremlin-Bicêtre, France
| | - Antoine Vieillard-Baron
- Medical and Surgical Intensive Care Unit, University Hospital Ambroise Paré, APHP, UMR 1018, UVSQ, Boulogne-Billancourt, France
| | - Waleed Alhazzani
- Critical Care and Internal Medicine Department, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
- Health Research Center, Ministry of Defense Health Services, Riyadh, Saudi Arabia
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Song L, Ye H, Lv Z, Liu Y, Lu Z, Chen J, Pan H, Cai L, Chen Y, Huang S, Zan X, Huang X, Yu C. Hexahistidine-metal assembly encapsulated fibroblast growth factor 21 for lipopolysaccharide-induced acute lung injury. Eur J Pharm Biopharm 2025; 208:114650. [PMID: 39870250 DOI: 10.1016/j.ejpb.2025.114650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 01/16/2025] [Accepted: 01/24/2025] [Indexed: 01/29/2025]
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) represents a spectrum of potentially fatal conditions that currently lack effective drug treatment. Recent researches suggest that Fibroblast Growth Factor 21 (FGF21) may protect against ALI/ARDS. However, the clinical use of FGF21 is limited by its rapid degradation, restricted targeting capabilities, and numerous adverse effects. Addressing this challenge, the study employs a pH-responsive nanoparticle delivery system known as Hexahistidine-metal Assembly (HmA) for administering FGF21. The entrapment efficiency (EE%) and loading capacity (LCwt%) of HmA exceed 90 % and 35 %, respectively, while the HmA@FGF21 nanoparticles exhibit an average size of 130 nm, a PDI value of approximately 0.28, and a zeta potential of 24 mV. In animal experiments, HmA@FGF21 administered in lipopolysaccharide (LPS)-induced lung injury significantly exceed those of standalone FGF21, including mitigating the pathological manifestations and reducing the wet/dry ratio, total protein concentration, and overall cell count in BALF of ALI, whether administered via the airway or intravenously. This therapeutic approach therefore shows promise for precise delivery of FGF21 to the lungs to treat ALI, and may offer a novel, and efficient method for delivery of potential pharmacological agents to address other lung diseases.
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Affiliation(s)
- Lanlan Song
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Huihui Ye
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Zhanghang Lv
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Yichen Liu
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Ziyi Lu
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Jun Chen
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Haofeng Pan
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Luqiong Cai
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China
| | - Yuxin Chen
- Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Shiqing Huang
- Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Xingjie Zan
- Joint Centre of Translational Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China.
| | - Xiaoying Huang
- Division of Pulmonary Medicine, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325000, China.
| | - Chang Yu
- Intervention Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
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Li H, Shan W, Zhao X, Sun W. Neutrophils: Linking Inflammation to Thrombosis and Unlocking New Treatment Horizons. Int J Mol Sci 2025; 26:1965. [PMID: 40076593 PMCID: PMC11901051 DOI: 10.3390/ijms26051965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/10/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Neutrophils play a key role in inflammatory responses and thrombosis, but their complex interactions in disease pathogenesis are not fully understood. This review examines the multifaceted roles of neutrophils, focusing on their activation, cytokine release, and formation of neutrophil extracellular traps (NETs), which contribute to host defense and thrombosis. We discuss the interaction between inflammation and coagulation, the direct effect of neutrophils on thrombus stability, and their involvement in pathological thrombotic diseases. The therapeutic potential of neutrophil drug loading in the treatment of thrombosis, as well as the clinical implications and future research directions, are highlighted. The aim of this review is to gain insight into the critical neutrophil-inflammation-thrombus axis and its potential as a therapeutic target for thrombotic diseases and to suggest possible directions for neutrophil-loaded drug therapy for thrombosis.
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Affiliation(s)
| | | | | | - Wei Sun
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China; (H.L.); (W.S.); (X.Z.)
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Guo N, Xia Y, He N, Zhang L, Liu J. IRGM Inhibits the AKT/mTOR Signaling Pathway by Interacting with TRIM21 to Alleviate Sepsis-Induced Acute Lung Injury. Inflammation 2025:10.1007/s10753-025-02265-w. [PMID: 39994091 DOI: 10.1007/s10753-025-02265-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 01/17/2025] [Accepted: 02/03/2025] [Indexed: 02/26/2025]
Abstract
Acute lung injury (ALI) is a severe complication of sepsis, and its underlying pathological mechanisms remain poorly understood. This study aims to investigate the role and mechanisms by which IRGM mediates autophagy through the regulation of the AKT/mTOR signaling pathway in sepsis-induced ALI. Initially, a sepsis-induced ALI mouse model was established using cecal ligation and puncture (CLP). Our results demonstrated that Irgm1 expression was significantly upregulated in the ALI model. Subsequently, Irgm1 was knocked down in vivo using AAV vectors, and changes in ALI symptoms were assessed. In vitro, a sepsis-induced ALI cell model was generated by stimulating A549 cells with lipopolysaccharide (LPS). The effects of IRGM overexpression on autophagy and apoptosis were evaluated, and its impact on the AKT/mTOR signaling pathway was analyzed. Furthermore, mass spectrometry and co-immunoprecipitation (COIP) experiments were conducted to explore the interaction between IRGM and TRIM21. In vivo results showed that Irgm1 knockout exacerbated CLP-induced ALI, as evidenced by a significant reduction in autophagic activity, increased apoptosis, and aberrant activation of the AKT/mTOR pathway. Further cellular experiments suggested that IRGM may enhance autophagy by inhibiting the AKT/mTOR signaling pathway, thereby attenuating LPS-induced cell damage. Additionally, COIP experiments revealed that IRGM interacts with TRIM21 to inhibit AKT/mTOR pathway activation, thereby promoting autophagy and mitigating sepsis-induced ALI. In conclusion, IRGM regulates autophagy through the AKT/mTOR signaling pathway and exerts protective effects in sepsis-induced ALI, suggesting that it may serve as a potential therapeutic target for sepsis-related ALI.
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Affiliation(s)
- Na Guo
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, China
| | - Yu Xia
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, China
| | - Nannan He
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, China
| | - Lei Zhang
- Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Center Hospital), Lanzhou, Gansu Province, China.
| | - Jian Liu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu Province, China.
- Gansu Provincial Maternity and Child-Care Hospital (Gansu Provincial Center Hospital), Lanzhou, Gansu Province, China.
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Khan S, Zaki A, Masood M, Khan A, Mohsin M, Verma A, Wilson PC, Ali S, Syed MA. Combating sepsis-induced acute lung injury: PARP1 inhibition mediates oxidative stress mitigation and miR-135a-5p/SMAD5/Nanog axis drives regeneration. Int Immunopharmacol 2025; 148:114166. [PMID: 39884084 DOI: 10.1016/j.intimp.2025.114166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 01/22/2025] [Accepted: 01/22/2025] [Indexed: 02/01/2025]
Abstract
PURPOSE The purpose of this study was to investigate the therapeutic potential of Poly (ADP-ribose) polymerase 1 (PARP1) inhibition combined with microRNA miR-135a-5p overexpression in sepsis-induced acute lung injury (ALI). Specifically, we aimed to elucidate combinatorial therapeutic potential of PARP1 inhibition in mitigating oxidative stress and inflammation across different models, simultaneously miR-135a-5p overexpression promoting regeneration through the SMAD5/Nanog axis. METHOD We used C57BL/6 mice to create Cecal Ligation Puncture (CLP) model of Sepsis-induced Acute Lung Injury. RAW264.7 murine macrophages and MLE12 (Mouse Lung Epithelial) cells were stimulated through Lipopolysaccharide (LPS) to induce inflammation. miR-135a-5p mimic Transfection confirmed using one-step Real time quantitative PCR (RT-qPCR). PARP1 inhibition confirmed by western blotting using Poly (ADP-ribose) (PAR) expression. Reactive oxygen Species (ROS) generation measured through Dichlorofluorescein diacetate (DCF-DA) dye using fluorescent microscopy and Nitric Oxide (NO) via spectrophotometry. Bronchoalveolar Lavage Fluid (BALF) cytokine analysis was done using Enzyme-linked immunosorbent assay (ELISA). miRNA mediated signaling, inflammatory markers and cytokines were determined using immunoblotting, RT-qPCR, and immunohistochemistry. miR-135a-5p target validation using dual-luciferase assay. RESULTS Our results demonstrated that PARP1 inhibition significantly reduced oxidative stress (**P < 0.01) and inflammatory markers in sepsis-induced lung injury models. Specifically, we observed decreased protein levels of inducible nitric oxide synthase (iNOS) (***P < 0.001), cyclooxygenase-2 (COX2) (*P < 0.05), phospho-Akt (*P < 0.05), and Tumor necrosis factor-Alpha (TNF-α) (*P < 0.05) mRNA expression. We observed significant reduction in ROS and NO generation in macrophages. Moreover, histopathological evidence suggested improved lung health. Concurrently, miR-135a-5p overexpression decreased the expression of SMAD5 (*P < 0.05) which in turns increased the expression of Nanog and related pluripotency genes in epithelial cells and mice, thus promoting regeneration and repair. CONCLUSION The combination of PARP1 inhibition and miR-135a-5p overexpression showed significant potential as a therapeutic intervention by reducing inflammation alongside stimulating regenerative environment in Sepsis-induced ALI.
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Affiliation(s)
- Salman Khan
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.
| | - Almaz Zaki
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India; Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India.
| | - Mohammad Masood
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.
| | - Aman Khan
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.
| | - Mohd Mohsin
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.
| | - Amit Verma
- Division of Diagnostic Innovation, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Parker C Wilson
- Division of Diagnostic Innovation, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Shakir Ali
- Department of Biochemistry, SCLS, Jamia Hamdard, New Delhi 110062, India
| | - Mansoor Ali Syed
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.
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Cai Y, Shang L, Zhou F, Zhang M, Li J, Wang S, Lin Q, Huang J, Yang S. Macrophage pyroptosis and its crucial role in ALI/ARDS. Front Immunol 2025; 16:1530849. [PMID: 40028334 PMCID: PMC11867949 DOI: 10.3389/fimmu.2025.1530849] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS) is a severe clinical syndrome characterized by high morbidity and mortality, primarily due to lung injury. However, the pathogenesis of ALI/ARDS remains a complex issue. In recent years, the role of macrophage pyroptosis in lung injury has garnered extensive attention worldwide. This paper reviews the mechanism of macrophage pyroptosis, discusses its role in ALI/ARDS, and introduces several drugs and intervening measures that can regulate macrophage pyroptosis to influence the progression of ALI/ARDS. By doing so, we aim to enhance the understanding of the mechanism of macrophage pyroptosis in ALI/ARDS and provide novel insights for its treatment.
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Affiliation(s)
- Yuju Cai
- Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Luorui Shang
- Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fangyuan Zhou
- Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengqi Zhang
- Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jinxiao Li
- Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shuhan Wang
- Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qifeng Lin
- Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jianghua Huang
- Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shenglan Yang
- Department of Clinical Nutrition, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Fan Q, Chen F, Chen M, Lin F, Xue Y. Predictive value of respiratory mechanics for the risk of unilateral pulmonary edema following minimally invasive cardiac surgery: An observational study. Medicine (Baltimore) 2025; 104:e41568. [PMID: 39960940 PMCID: PMC11835078 DOI: 10.1097/md.0000000000041568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 01/30/2025] [Indexed: 02/20/2025] Open
Abstract
This study aimed to investigate the predictive effect of static lung compliance (SLC) and airway resistance (AR) in patients undergoing minimally invasive cardiac surgery (MICS) with unilateral pulmonary edema (UPE). A total of 245 patients who underwent MICS via cardiopulmonary bypass and minimal right lateral thoracic incision port access were enrolled, with immediate postoperative SLC and AR data collected upon intensive care unit (ICU) admission. Cutoff values for grouping patients into high (H-) and low (L-) compliance/resistance categories were determined using receiver-operating characteristic curves and Youden indexes. The primary outcome was the incidence of radiographically and clinically defined UPE within the first 24 hours postoperatively, while the secondary outcomes included duration of mechanical ventilation, length of ICU stay, total hospitalization days, in-hospital mortality, and the highest sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation II (APACHE-II) scores within the first 24 hours post-surgery. Results showed that patients in the L-compliance group (SLC < 40 mL/cmH2O) had longer durations of mechanical ventilation, length of ICU stay, and total hospitalization days, along with higher SOFA and APACHE-II scores compared to those in the H-compliance group (SLC ≥ 40 mL/cmH2O) (P < .05), although there was no significant difference in in-hospital mortality. Conversely, patients in the H-resistance group (AR ≥ 11 cm H2O/[L·s]) exhibited longer durations of mechanical ventilation, length of ICU stay, and total hospitalization days, as well as significantly higher SOFA, APACHE-II scores, but lower in-hospital mortality rates than those in the L-resistance group (AR < 11 cm H2O/[L·s]) (P < .05). In summary, immediate postoperative SLC < 40 mL/cm H2O and AR > 11 cm H2O/(L·s) are potentially valuable indicators for predicting postoperative UPE in patients undergoing MICS.
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Affiliation(s)
- Qiaolian Fan
- Fourth Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, Fujian, China
| | - Feng Chen
- Department of Emergency, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, Fujian, China
| | - Mingguang Chen
- Fourth Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, Fujian, China
| | - Fenghui Lin
- Fourth Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, Fujian, China
| | - Yimin Xue
- Fourth Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, Fujian, China
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Celik M, Koca M, Halici Z, Tavaci T, Halici H, Ozkaraca M, Karakoy Z, Bayraktutan Z. The Effect of Inhaled Ozone Therapy in Two-Hit Rat Model of Lipopolysaccharides-Induced Acute Lung Injury and Bleomycin-Induced Pulmonary Fibrosis. Protein J 2025:10.1007/s10930-024-10247-4. [PMID: 39920533 DOI: 10.1007/s10930-024-10247-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2024] [Indexed: 02/09/2025]
Abstract
Considering the limited treatment options for acute lung injury (ALI) and pulmonary fibrosis (PF), ozone treatment may be promising as a new immunological agent with its ability to modulate cytokines and interferons. We aimed to investigate the effects of inhaled ozone therapy on both ALI and PF in rat models. A total of 48 albino Wistar male rats were included in the study. Lipopolysaccharide (LPS) was used to induce the ALI model, and bleomycin was used for the PF model. The effects of inhaled ozone (O3) were investigated using the ELISA method. Hematoxylin&eosin staining, Masson's trichrome staining, and immunohistochemical methods were used for histopathological evaluation. The Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), and Nuclear Factor kappa B subunit p65 (NF-κB p65) levels in the ALI + 0.08 ppm O3, ALI + 0.12 ppm O3, PF + 0.08 ppm O3, and PF + 0.12 ppm O3 groups statistically decreased to the same extent and approached the levels of control animals. It was observed that IL-1β, IL-6, TNF-α, and NF-κB p65 levels in lung tissues were significantly and dose-dependently decreased compared to the untreated PF and ALI groups, respectively. While fibrosis was severe in the PF + 0.08 ppm O3 group, it decreased to more moderate levels in the PF + 0.12 ppm O3 group. The cytokine levels confirmed that inhaled ozone protected the lungs from both ALI and the development of PF.
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Affiliation(s)
- Mine Celik
- Department of Anesthesiology and Reanimation, Istanbul Provincial Health Directorate, Istanbul Haseki Education And Research Hospital, Istanbul, 34130, Turkey.
| | - Mehmet Koca
- Management Services General Directorate, Ministry of Health, 06800, Ankara, Turkey
| | - Zekai Halici
- Department of Pharmacology, Faculty of Medicine, Ataturk University, 25240, Erzurum, Turkey
| | - Taha Tavaci
- Department of Pharmacology, Faculty of Medicine, Sakarya University, 54050, Sakarya, Turkey
| | - Hamza Halici
- Department of Hınıs Vocational Training School, Ataturk University, 25600, Erzurum, Turkey
| | - Mustafa Ozkaraca
- Department of Pathology, Faculty of Veterinarian, Cumhuriyet University, 58070, Sivas, Turkey
| | - Zeynep Karakoy
- Department of Pharmacology, Faculty of Pharmacy, Erzincan Binali Yıldırım University, 24002, Erzincan, Turkey
| | - Zafer Bayraktutan
- Department of Biochemistry, Faculty of Medicine, Ataturk University, 25040, Erzurum, Turkey
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Wang Y, Wang W, Zhang Y, Fleishman JS, Wang H. Targeting ferroptosis offers therapy choice in sepsis-associated acute lung injury. Eur J Med Chem 2025; 283:117152. [PMID: 39657462 DOI: 10.1016/j.ejmech.2024.117152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 10/06/2024] [Accepted: 12/06/2024] [Indexed: 12/12/2024]
Abstract
Sepsis-associated acute lung injury (SALI) is a common complication of sepsis, consisting of a dysfunctional host response to infection-mediated heterogenous complexes. SALI is reported in up to 50 % of patients with sepsis and causes poor outcomes. Despite high incidence, there is a lack of understanding in its pathogenesis and optimal treatment. A better understanding of the molecular mechanisms underlying SALI may help produce better therapeutics. The effects of altered cell-death mechanisms, such as non-apoptotic regulated cell death (RCD) (i.e., ferroptosis), on the development of SALI are beginning to be discovered, while targeting ferroptosis as a meaningful target in SALI is increasingly being recognized. Here, we outline how a susceptible lung alveoli may develop SALI. Then we discuss the general mechanisms underlying ferroptosis, and how it contributes to SALI. We then outline the chemical structures of the emerging agents or compounds that can protect against SALI by inhibiting ferroptosis, summarizing their potential pharmacological effects. Finally, we highlight key limitations and possible strategies to overcome them. This review suggests that a detailed mechanistic and biological understanding of ferroptosis can foster the development of pharmacological antagonists in the treatment of SALI.
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Affiliation(s)
- Yu Wang
- Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China
| | - Weixue Wang
- Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China
| | - Yi Zhang
- Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China
| | - Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
| | - Hongquan Wang
- Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, China.
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Xu Z, Liu X, Zhang L, Yan X. Comparative outcomes of corticosteroids, neuromuscular blocking agents, and inhaled nitric oxide in ARDS: a systematic review and network meta-analysis. Front Med (Lausanne) 2025; 12:1507805. [PMID: 39963433 PMCID: PMC11831700 DOI: 10.3389/fmed.2025.1507805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 01/13/2025] [Indexed: 02/20/2025] Open
Abstract
Objectives Acute respiratory distress syndrome (ARDS) is associated with high rates of morbidity and mortality. However, the evidence regarding the effectiveness of commonly used treatments, including corticosteroids, neuromuscular blocking agents (NMBAs), and inhaled nitric oxide (iNO), remains uncertain. Therefore, this study aimed to compare and rank these three treatments to identify the most effective option. Data sources We searched PubMed, Embase, Cochrane Library, and Web of Science for clinical trials from the earliest records to 1 May 2024. Study selection and data extraction Clinical trials evaluating three interventions compared with the control group for ARDS were included, with restrictions on any language. Data were extracted by two independent reviewers. Frequentist network meta-analysis (NMA) was performed to identify the most effective intervention, and treatments were ranked using the surface under the cumulative ranking (SUCRA) curve. The primary outcome was 28-day mortality, while secondary outcomes included ventilator-free days up to 28 days, ICU mortality, in-hospital mortality, and the incidence of new infection events. Data synthesis Data from 26 clinical trials encompassing 5,071 patients were analyzed. Vecuronium bromide was the most effective strategy for reducing 28-day mortality compared to conventional treatment, iNO, methylprednisolone, and placebo (OR 0.38, 95% CI 0.15-1.00, and OR 0.30, 95% CI 0.10-0.85 and OR 0.25, 95% CI 0.08-0.74 and OR 0.23, 95% CI 0.08-0.65; SUCRA: 96.6%). Dexamethasone was identified as the most effective treatment option for increasing ventilator-free days at 28 days compared to conventional therapy and cisatracurium (MD 3.60, 95% CI 1.77-5.43, and MD 3.40, 95% CI 0.87-5.92; SUCRA: 93.2%). Methylprednisolone demonstrated the highest effectiveness for preventing ICU mortality (SUCRA: 88.5%). Although dexamethasone, cisatracurium, conventional therapy, methylprednisolone, and iNO treatment did not show significant superiority in reducing in-hospital mortality, dexamethasone showed the highest probability of being the most effective treatment option (SUCRA: 79.7%). Furthermore, dexamethasone treatment showed the highest safety in reducing the incidence of new infection events compared with placebo and iNO (OR 0.61, 95% CI 0.42-0.88, and OR 0.33, 95% CI 0.19-0.58; SUCRA: 91.8%). Conclusion This NMA suggests that corticosteroids may provide benefits to patients with ARDS. While the application of NMBAs may reduce 28-day mortality, iNO did not demonstrate a significant beneficial effect as a therapeutic measure. Systematic review registration PROSPERO, CRD42022333165 https://www.crd.york.ac.uk/PROSPERO/.
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Affiliation(s)
- Zhiyuan Xu
- Department of Emergency Medicine, Xuzhou No. 1 People’s Hospital, Xuzhou, Jiangsu, China
| | - Xiao Liu
- Department of Emergency Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Liang Zhang
- Department of Emergency Medicine, Xuzhou No. 1 People’s Hospital, Xuzhou, Jiangsu, China
| | - Xianliang Yan
- Department of Emergency Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
- Department of Emergency Medicine, Suining County People’s Hospital, Xuzhou, Jiangsu, China
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