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Alzahrani HA, Corcione N, Alghamdi SM, Alhindi AO, Albishi OA, Mawlawi MM, Nofal WO, Ali SM, Albadrani SA, AlJuaid MA, Alshehri AM, Alzluaq MZ. Driving pressure in acute respiratory distress syndrome for developing a protective lung strategy: A systematic review. World J Crit Care Med 2025; 14:101377. [DOI: 10.5492/wjccm.v14.i2.101377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 12/15/2024] [Accepted: 01/03/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is a critical condition characterized by acute hypoxemia, non-cardiogenic pulmonary edema, and decreased lung compliance. The Berlin definition, updated in 2012, classifies ARDS severity based on the partial pressure of arterial oxygen/fractional inspired oxygen fraction ratio. Despite various treatment strategies, ARDS remains a significant public health concern with high mortality rates.
AIM To evaluate the implications of driving pressure (DP) in ARDS management and its potential as a protective lung strategy.
METHODS We conducted a systematic review using databases including EbscoHost, MEDLINE, CINAHL, PubMed, and Google Scholar. The search was limited to articles published between January 2015 and September 2024. Twenty-three peer-reviewed articles were selected based on inclusion criteria focusing on adult ARDS patients undergoing mechanical ventilation and DP strategies. The literature review was conducted and reported according to PRISMA 2020 guidelines.
RESULTS DP, the difference between plateau pressure and positive end-expiratory pressure, is crucial in ARDS management. Studies indicate that lower DP levels are significantly associated with improved survival rates in ARDS patients. DP is a better predictor of mortality than tidal volume or positive end-expiratory pressure alone. Adjusting DP by optimizing lung compliance and minimizing overdistension and collapse can reduce ventilator-induced lung injury.
CONCLUSION DP is a valuable parameter in ARDS management, offering a more precise measure of lung stress and strain than traditional metrics. Implementing DP as a threshold for safety can enhance protective ventilation strategies, potentially reducing mortality in ARDS patients. Further research is needed to refine DP measurement techniques and validate its clinical application in diverse patient populations.
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Affiliation(s)
- Hassan A Alzahrani
- Department of Respiratory Care, Medical Cities at the Minister of Interior, Riyadh 13321, Saudi Arabia
| | - Nadia Corcione
- Interventional Pulmonology, Antonio Cardarelli Hospital, Naples, Italy
| | - Saeed M Alghamdi
- Department of Clinical Technology, Respiratory Care Program, Umm-Al Qura University, Makkah al Mukarramah 21599, Saudi Arabia
| | - Abdulghani O Alhindi
- Respiratory Therapy Unit, Security Forced Hospital Program, Makkah al Mukarramah 26955, Saudi Arabia
| | - Ola A Albishi
- Department of Medical Affairs, Security Forced Hospital Program, Makkah al Mukarramah 25911, Saudi Arabia
| | - Murad M Mawlawi
- Department of Intensive Care Unit and Medical Affairs, Security Forced Hospital Program, Makkah al Mukarramah 23455, Saudi Arabia
| | - Wheb O Nofal
- Department of Pharmacy, Security Forced Hospital Program, Makkah al Mukarramah 23455, Saudi Arabia
| | - Samah M Ali
- Department of Internal Medicine, Security Forced Hospital Program, Makkah al Mukarramah 21955, Saudi Arabia
| | - Saad A Albadrani
- Department of Respiratory Therapy, King Faisal Medical Complex, Taif 29167, Saudi Arabia
| | - Meshari A AlJuaid
- Department of Respiratory Therapy, King Faisal Medical Complex, Taif 29167, Saudi Arabia
| | - Abdullah M Alshehri
- Department of Respiratory Therapy, King Fahad, General Hospital, Taif 29167, Saudi Arabia
| | - Mutlaq Z Alzluaq
- Department of Respiratory Therapy, East Jeddah Hospital, First Jeddah Cluster, Jeddah 23235, Saudi Arabia
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Liu Z, Lei Y, Zuo J, Zhang R, Du H, Hu H, Zheng J, Yang P, Zhao D. Activated Notch1 promotes macrophage polarization and exacerbates sepsis-induced acute lung injury via β-catenin/NF-κB signaling. Biochem Pharmacol 2025; 236:116892. [PMID: 40127740 DOI: 10.1016/j.bcp.2025.116892] [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: 12/17/2024] [Revised: 02/26/2025] [Accepted: 03/21/2025] [Indexed: 03/26/2025]
Abstract
Sepsis-induced acute lung injury (ALI) is a critical condition characterized by excessive inflammation, with macrophage polarization playing a pivotal role in its pathogenesis. In this study, we constructed myeloid-specific Notch1 knockout mice, overexpressed the Notch intracellular domain (NICD), and inhibited β-catenin using XAV939 to investigate the impact and mechanisms of Notch1 regulation in macrophage polarization and inflammatory responses in cecal ligation and puncture (CLP)-induced septic mice. The results demonstrated that Notch1 knockout significantly reduced M1 macrophage polarization, alleviated systemic inflammation, mitigated lung injury, and improved survival in septic mice. In sepsis, Notch1 enhances β-catenin expression, which synergizes with the NF-κB pathway to promote M1 polarization and pro-inflammatory cytokine production. Specifically, NICD interacts with β-catenin in macrophages, amplifying NF-κB activation and its nuclear translocation. These results demonstrate that the Notch1 signaling pathway plays a pivotal role in regulating macrophage phenotypic switching, highlighting its potential as a therapeutic target for attenuating sepsis-associated ALI through immune homeostasis restoration.
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Affiliation(s)
- Zhi Liu
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yuxi Lei
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Jing Zuo
- The Research Centre of Anesthesiology and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Ruiyu Zhang
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Hui Du
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Huizhi Hu
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Junwen Zheng
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Pu Yang
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Children's Digital Health and Data Center of Wuhan University, Wuhan 430071, China.
| | - Dongchi Zhao
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Children's Digital Health and Data Center of Wuhan University, Wuhan 430071, China.
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3
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Fang Y, Qiu J, Xu Y, Wu Q, Huo XC, Liu SH. Ophiopogonin D Alleviates Sepsis-Induced Acute Lung Injury Through Improving Microvascular Endothelial Barrier Dysfunction via Inhibition of HIF-1α-VEGF Pathway. Cell Biochem Biophys 2025; 83:2519-2531. [PMID: 39890704 DOI: 10.1007/s12013-024-01661-7] [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] [Accepted: 12/23/2024] [Indexed: 02/03/2025]
Abstract
Pulmonary endothelial barrier dysfunction is a hallmark of sepsis-induced acute lung injury (ALI). Ophiopogonin D (OP-D), isolated from the roots of Ophiopogon japonicus, is involved in regulating inflammation, apoptosis and intestinal permeability. However, the role of OP-D in ALI has not been reported and the related mechanisms remain unclear. In this study, cecal ligation and puncture (CLP) was used to establish a septic ALI model in mice. We found that OP-D effectively alleviated lung pathological damage. Moreover, OP-D decreased pulmonary microvascular permeability, restrained the inflammatory response and apoptosis in murine lung tissues and LPS-exposed PMVECs. Specifically, OP-D exerted the beneficial effects via mediating the inactivation of HIF-1α-VEGF pathway, which was partly abrogated by the overexpression of HIF-1α. Collectively, our findings showed that OP-D protected against sepsis-induced ALI through improving pulmonary microvascular endothelial barrier dysfunction via suppressing HIF-1α-VEGF pathway.
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Affiliation(s)
- Yi Fang
- Department of Anesthesiology, Affiliated Changsha Central Hospital to Nanhua University, Changsha, 410016, Hunan, PR China
| | - Jun Qiu
- The first-affiliated hospital of Hunan normal university (The second tumor ward, Hunan Provincial People's Hospital), Changsha, 410006, Hunan, PR China
| | - Yu Xu
- Department of Anesthesiology, Affiliated Changsha Central Hospital to Nanhua University, Changsha, 410016, Hunan, PR China
| | - Qing Wu
- Department of Anesthesiology, Affiliated Changsha Central Hospital to Nanhua University, Changsha, 410016, Hunan, PR China
| | - Xing-Chen Huo
- Department of Anesthesiology, Affiliated Changsha Central Hospital to Nanhua University, Changsha, 410016, Hunan, PR China
| | - Song-Hua Liu
- Department of Anesthesiology, Affiliated Changsha Central Hospital to Nanhua University, Changsha, 410016, Hunan, PR China.
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4
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Grunwell JR, Stephenson ST, Dallalio GA, Diani BA, Zaworski C, Jordan N, Fitzpatrick AM. Development of an acute lung injury model for drug testing. Sci Rep 2025; 15:17703. [PMID: 40399348 PMCID: PMC12095525 DOI: 10.1038/s41598-025-02078-9] [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: 01/15/2025] [Accepted: 05/12/2025] [Indexed: 05/23/2025] Open
Abstract
A challenge that limits our understanding of the underlying pathobiology of pediatric acute respiratory distress syndrome (PARDS) is the lack of a preclinical airway model that can be leveraged for the study of mechanisms and specific molecules for drug testing. We developed a physiologic model system of the small airways for mechanistic application in PARDS using a co-culture of primary human-derived small airway epithelial cells (SAECs) cultured at the air-liquid interface and umbilical vein endothelial cells in a transwell system. The model was validated by exposing the SAECs to a rhinovirus infection, to an inflammatory lung insult using a mixture of cytokines found in ARDS (cytomix), and to airway fluid samples from children with different severity strata of PARDS. We used a combination of transepithelial electrical resistance, immunofluorescence confocal microscopy of tight junctions, targeted gene expression, and cytokine responses to evaluate the model to the aforementioned insults. We then use the model in drug testing and show the reduction in IL-6 expression in conditioned media and STAT3 phosphorylation following co-treatment of SAECs with cytomix and the Janus kinase inhibitor (JAKi) baricitinib. This model enables mechanistic studies of airway pathobiology and may serve as a novel drug testing platform for PARDS.
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Affiliation(s)
- Jocelyn R Grunwell
- Division of Critical Care Medicine, Children's Healthcare of Atlanta, Arthur M. Blank Hospital, 2220 North Druid Hills Rd NE, Atlanta, GA, 30329, USA.
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
| | - Susan T Stephenson
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Gail A Dallalio
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Badiallo A Diani
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Celena Zaworski
- Division of Critical Care Medicine, Children's Healthcare of Atlanta, Arthur M. Blank Hospital, 2220 North Druid Hills Rd NE, Atlanta, GA, 30329, USA
| | - Natalie Jordan
- Division of Critical Care Medicine, Children's Healthcare of Atlanta, Arthur M. Blank Hospital, 2220 North Druid Hills Rd NE, Atlanta, GA, 30329, USA
| | - Anne M Fitzpatrick
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
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5
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Kim OH, Kim TW, Kang H, Jeon TJ, Chang ES, Lee HJ, Kim WY. Early, very high-dose, and prolonged vitamin C administration in murine sepsis. Sci Rep 2025; 15:17513. [PMID: 40394136 PMCID: PMC12092791 DOI: 10.1038/s41598-025-02622-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 05/14/2025] [Indexed: 05/22/2025] Open
Abstract
This proof-of-concept study aimed to assess the optimal timing, dosing, and duration of vitamin C administration to increase survival and attenuate organ injuries in murine sepsis. Mice were randomized to receive ascorbic acid (AscA) at 1 or 6 h after cecal ligation and puncture (CLP). At each time point, mice randomly received AscA for 4 or 8 d. Mice were assigned to sham and CLP groups, as well as CLP + AscA groups that were treated with AscA at doses of 90, 180, or 360 mg/kg/d. The survival curves diverged significantly when AscA was injected at doses of 180 or 360 mg/kg/d for 8 d, although this was not observed when the treatment was limited to 4 d. AscA at doses of 180 or 360 mg/kg/d for 8 d preserved lung architecture while attenuating the abnormal expression of tight junction proteins. Kidney and liver injuries were evident in CLP mice, with elevated expression of biomarkers and inflammatory mediators; however, exposure to AscA at doses of 180 or 360 mg/kg/d for 8 d improved the histological changes and decreased biomarker expression levels. Very high-dose and prolonged vitamin C administration may potentially play a role in the management of sepsis-associated organ injuries.
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Affiliation(s)
- Ok-Hyeon Kim
- Department of Anatomy and Cell Biology, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Tae Wan Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Hana Kang
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Tae Jin Jeon
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Eun Seo Chang
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Hyun Jung Lee
- Department of Anatomy and Cell Biology, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
- Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea.
| | - Won-Young Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
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6
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Lim MJ, Kim SJ, Jo A, Kim SW. Enhanced application potential of alveolar organoids through epithelial and niche cell interactions. Sci Rep 2025; 15:17538. [PMID: 40394147 PMCID: PMC12092580 DOI: 10.1038/s41598-025-01853-y] [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: 02/10/2025] [Accepted: 05/08/2025] [Indexed: 05/22/2025] Open
Abstract
Recent studies have focused on understand lung repair mechanisms, which are critical for treating respiratory diseases. In this study, we develop alveolar organoids to investigate the complex interactions between alveolar epithelial cells, niche fibroblasts and macrophages, which are essential for lung development, maintenance and repair, especially under physiological injury. Our results suggest that alveolar organoids may be a model for epithelial cell regeneration and the inflammatory response in lung tissue. Alveolar organoid studies can also serve as models for various lung injuries and demonstrate mechanisms in the injured human lung.
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Affiliation(s)
- Min Jae Lim
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Medical Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Joon Kim
- Division of Pulmonology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Postech-Catholic Biomedical Engineering Institute, Collage of Medicine, The Catholic University of Korea, Songeui Multiplex Hall, Seoul, Korea
| | - Ayoung Jo
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
| | - Sung Won Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
- Department of Medical Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.
- Postech-Catholic Biomedical Engineering Institute, Collage of Medicine, The Catholic University of Korea, Songeui Multiplex Hall, Seoul, Korea.
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7
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Han D, Zhang Y, Yang H, Fang J, Li G, Zeng L, Tang H, Li T. Diagnostic value of ultrasonic indicators for assessing acute lung injury severity. Sci Rep 2025; 15:17256. [PMID: 40383807 PMCID: PMC12086212 DOI: 10.1038/s41598-025-99848-2] [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: 08/13/2024] [Accepted: 04/23/2025] [Indexed: 05/20/2025] Open
Abstract
Systemic volume changes during acute lung injury (ALI) are closely related to lung injury severity, disease progression, and treatment methods. Twenty-one goats were divided into control, mild injury, and severe injury groups via oleic acid injection. Carotid ultrasound measured carotid diameter and corrected flow time (FTc), while cardiac ultrasound assessed aortic and pulmonary artery velocity-time integral (VTI). Post-euthanasia at 6 h, lung wet-to-dry (W/D) ratio and pathological scores were analyzed. Statistical trends, correlations between ultrasound parameters and lung injury markers, and diagnostic performance via ROC analysis were evaluated. The severe injury group had significantly higher lung W/D ratios and pathological scores than the mild injury group. Carotid ultrasound showed a progressive decrease in carotid diameter and FTc post-injury, with FTc significantly lower in the severe injury group at 6-h. FTc was negatively correlated with lung W/D ratio and pathological scores. Cardiac ultrasound indicated a decreasing trend in aortic and pulmonary artery VTI post-injury, with pulmonary artery VTI significantly lower in the severe injury group at all times and negatively correlated with lung W/D ratio and pathological scores. ROC analysis showed that pulmonary artery VTI had the highest area under the curve (AUC), with values greater than 0.8 at all time points. The combined use of pulmonary artery VTI and carotid FTc had AUC values greater than 0.85 at all time points, peaking at 6-h (AUC = 0.951). In conclusion, pulmonary artery VTI is an excellent indicator for evaluating ALI severity post-injury, and the combination of pulmonary artery VTI and carotid FTc shows strong diagnostic performance for assessing ALI severity.
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Affiliation(s)
- Dong Han
- Department of Ultrasound Diagnosis, Daping Hospital, Army Medical University, Chongqing, China
| | - Yingying Zhang
- Department of Ultrasound Diagnosis, Daping Hospital, Army Medical University, Chongqing, China
| | - Huan Yang
- Department of Ultrasound Diagnosis, Daping Hospital, Army Medical University, Chongqing, China
| | - Jingqin Fang
- Department of Ultrasound Diagnosis, Daping Hospital, Army Medical University, Chongqing, China
| | - Guanhua Li
- Department of Weapon Injury Bioeffect Assessment, Daping Hospital, Army Medical University, Chongqing, China
| | - Ling Zeng
- Depatment of Field Medical Equiment, Daping Hospital, Army Medical University, Chongqing, China
| | - Hao Tang
- Department of Critical Care Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Tao Li
- Department of Ultrasound Diagnosis, Daping Hospital, Army Medical University, Chongqing, China.
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8
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D'Ardes D, Deana C, Boccatonda A, Biasucci DG, Cipollone F, Castro-Sayat M, Colaianni-Alfonso N, Gallardo A, Vetrugno L. Lung Ultrasound After COVID-19: A Pivotal Moment for Clinical Integration-Navigating Challenges and Seizing Opportunities. Healthcare (Basel) 2025; 13:1148. [PMID: 40427984 DOI: 10.3390/healthcare13101148] [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: 02/21/2025] [Revised: 04/20/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Lung ultrasound (LUS) has emerged as a valuable bedside decision-making tool, particularly since the COVID-19 pandemic, with applications in diagnosing pneumonia, managing fluid, and monitoring interstitial lung diseases (ILDs) and acute respiratory distress syndrome (ARDS), ultimately improving patient outcomes. Its repeatability, environmental safety, and reduced radiation exposure make it ideal for vulnerable populations and resource-limited settings. However, challenges such as inadequate documentation and a lack of standardized reporting formats limit its widespread adoption. The evolution of technology offers different possibilities, and improvements in software open up a range of possibilities, but this contrasts with the lack of postgraduate and undergraduate training and formal accreditation. This review addresses the impact of lung ultrasound through the course of air-liquid ratio impairment, crossing different clinical scenarios and exploring the challenges and opportunities for the implementation of lung ultrasound in the post-COVID era.
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Affiliation(s)
- Damiano D'Ardes
- Institute of "Clinica Medica", Department of Medicine and Aging Science, "G. D'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
- Department of Anesthesiology, Critical Care Medicine and Emergency, SS. Annunziata Hospital, 66100 Chieti, Italy
| | - Cristian Deana
- Department of Anesthesia and Intensive Care, Health Integrated Agency of Friuli Centrale, 33100 Udine, Italy
| | - Andrea Boccatonda
- Diagnostic and Therapeutic Interventional Ultrasound Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Daniele Guerino Biasucci
- Department of Clinical Science and Translational Medicine, "Tor Vergata" University of Rome, 00133 Rome, Italy
| | - Francesco Cipollone
- Institute of "Clinica Medica", Department of Medicine and Aging Science, "G. D'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
| | - Mauro Castro-Sayat
- Intermediate Respiratory Care Unit, Juan A. Fernandez Hospital, Buenos Aires C1425, Argentina
| | | | - Adrián Gallardo
- Department of Kinesiology and Respiratory Care, "Sanatorio Clínica Modelo de Morón", Morón C1015, Argentina
- Department of Health Sciences, Kinesiology and Physiatry, National University of La Matanza, San Justo B1754, Argentina
| | - Luigi Vetrugno
- Department of Emergency, Health Integrated Agency of Friuli Centrale, 33100 Udine, Italy
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, 66100 Chieti, Italy
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9
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Riedmann KJ, Meegan JE, Afzal A, Cervantes-Cruz Y, Obeidalla S, Bogart AM, Ware LB, Shaver CM, Bastarache JA. Oxidized Cell-Free Hemoglobin Induces Mitochondrial Dysfunction by Activation of the Mitochondrial Permeability Transition Pore in the Pulmonary Microvasculature. Microcirculation 2025; 32:e70012. [PMID: 40394906 DOI: 10.1111/micc.70012] [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: 01/03/2025] [Revised: 04/02/2025] [Accepted: 05/08/2025] [Indexed: 05/22/2025]
Abstract
OBJECTIVE Cell-free hemoglobin (CFH) is released into the circulation during sepsis where it can redox cycle from the ferrous 2+ to ferric 3+ and disrupt endothelial function, but the mechanisms of CF-mediated endothelial dysfunction are unknown. We hypothesized that oxidized CFH induces mitochondrial dysfunction via the mitochondrial permeability transition pore (mPTP) in pulmonary endothelial cells, leading to the release of mitochondrial DNA (mtDNA). METHODS Human lung microvascular endothelial cells were treated with CFH2+/CFH3+. We measured mitochondrial mPTP activation (flow cytometry), network and mass (immunostaining), structure (electron microscopy), mtDNA release (PCR), and oxygen consumption rate (OCR; Seahorse). Plasma from critically ill patients and conditioned cell media were quantified for mtDNA and CFH. RESULTS CFH3+ disrupted the mitochondrial network, activated the mPTP (1434 (874-1642) vs. 2302 (1729-2654) mean fluorescent intensity, p = 0.02), increased the spare respiratory capacity (30.61 (29.36-37.78) vs. 7.83 (3.715-10.63) OCR, p = 0.004), and caused the release of mtDNA. CFH was associated with circulating mtDNA (R2 = 0.1912, p = 0.0077) in plasma from critically ill patients. CONCLUSION CFH3+, not CFH2+, is the primary driver of CFH-induced lung microvascular mitochondrial dysfunction. Activation of the mPTP and the release of mtDNA are a feature of CFH3+ mediated injury.
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Affiliation(s)
- Kyle J Riedmann
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jamie E Meegan
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Aqeela Afzal
- Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Yatzil Cervantes-Cruz
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sarah Obeidalla
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Avery M Bogart
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Lorraine B Ware
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Ciara M Shaver
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA
| | - Julie A Bastarache
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
- Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, USA
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10
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Hamishegi FS, Singh R, Baruah D, Chamberlin J, Hamouda M, Akkaya S, Kabakus I. Drug-induced Acute Lung Injury: A Comprehensive Radiologic Review. J Thorac Imaging 2025; 40:e0816. [PMID: 39330765 DOI: 10.1097/rti.0000000000000816] [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: 09/28/2024]
Abstract
Drug-induced acute lung injury is a significant yet often underrecognized clinical challenge, associated with a wide range of therapeutic agents, including chemotherapy drugs, antibiotics, anti-inflammatory drugs, and immunotherapies. This comprehensive review examines the pathophysiology, clinical manifestations, and radiologic findings of drug-induced acute lung injury across different drug categories. Common imaging findings are highlighted to aid radiologists and clinicians in early recognition and diagnosis. The review emphasizes the importance of immediate cessation of the offending drug and supportive care, which may include corticosteroids. Understanding these patterns is crucial for prompt diagnosis and management, potentially improving patient outcomes.
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Affiliation(s)
| | - Ria Singh
- Osteopathic Medical School, Kansas City University, Kansas, MO
| | - Dhiraj Baruah
- Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC
| | - Jordan Chamberlin
- Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC
| | - Mohamed Hamouda
- Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC
| | - Selcuk Akkaya
- Department of Radiology and Radiological Science, Karadeniz Technical University, Trabzon, Turkey
| | - Ismail Kabakus
- Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC
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11
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Zhang Y, Zhang G, Dong B, Pandeya A, Cui J, Valenca SDS, Yang L, Qi J, Chai Z, Wu C, Kirchhofer D, Shiroishi T, Khasawneh F, Tao M, Shao F, Waters CM, Wei Y, Li Z. Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure. Cell Rep 2025; 44:115479. [PMID: 40158217 PMCID: PMC12087274 DOI: 10.1016/j.celrep.2025.115479] [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: 07/17/2024] [Revised: 12/16/2024] [Accepted: 03/06/2025] [Indexed: 04/02/2025] Open
Abstract
The NAIP/NLRC4 inflammasome plays a pivotal role in the defense against bacterial infections, with its in vivo physiological function primarily recognized as driving inflammation in immune cells. Acute lung injury (ALI) is a leading cause of mortality in sepsis. In this study, we identify that the NAIP/NLRC4 inflammasome is highly expressed in both macrophages and pulmonary fibroblasts and that pyroptosis of these cells plays a critical role in lung injury. Mice challenged with gram-negative bacteria or flagellin developed lethal lung injury, characterized by reduced blood oxygen saturation, disrupted lung barrier function, and escalated inflammation. Flagellin-induced lung injury was protected in caspase-1 or GSDMD-deficient mice. These findings enhance our understanding of the NAIP/NLRC4 inflammasome's (patho)physiological function and highlight the significant role of inflammasome activation and pyroptosis in ALI during sepsis.
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Affiliation(s)
- Yan Zhang
- Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA; Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Guoying Zhang
- Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Brittany Dong
- Department of Physiology, University of Kentucky, Lexington, KY 40506, USA
| | - Ankit Pandeya
- Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA; Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA
| | - Jian Cui
- Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40506, USA
| | | | - Ling Yang
- Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Jiaqian Qi
- Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Zhuodong Chai
- Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Congqing Wu
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40506, USA; Department of Surgery, University of Kentucky, Lexington, KY 40506, USA
| | - Daniel Kirchhofer
- Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080, USA
| | | | - Fadi Khasawneh
- Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Min Tao
- Department of Oncology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Feng Shao
- National Institute of Biological Sciences, Beijing 102206 China
| | - Christopher M Waters
- Department of Physiology, University of Kentucky, Lexington, KY 40506, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40506, USA
| | - Yinan Wei
- Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Zhenyu Li
- Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX 77843, USA.
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12
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Gui L, Cao H, Zheng M, Pan Y, Ning C, Cheng M. Early acetaminophen administration is associated with lower mortality among ARDS patients after coronary artery bypass grafting: a retrospective study. J Cardiothorac Surg 2025; 20:209. [PMID: 40251639 PMCID: PMC12007132 DOI: 10.1186/s13019-025-03421-x] [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: 11/27/2024] [Accepted: 04/06/2025] [Indexed: 04/20/2025] Open
Abstract
BACKGROUND Acetaminophen (APAP) is widely used in the treatment of patients after surgery, but the prognosis of patients with coronary artery bypass grafting (CABG)-related acute respiratory distress syndrome (CABG-ARDS) is still unclear. This study aims to explore the role of APAP in the management of CABG related ARDS. METHODS We collected clinical data on patients with CABG-ARDS from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The primary outcome was early mortality after ARDS, and the secondary outcomes were length of hospital stay and duration of mechanical ventilation (MV). Multivariate logistic regression and Cox regression models were used for statistical analysis, and inverse probability processing weighting (IPTW), overlap weighting (OW) and propensity score matching (PSM) were used to explore the robustness of the outcomes. RESULTS A total of 5459 patients were enrolled in the analysis. Multivariate logistic regression analysis revealed that the 14-day mortality in APAP group was significantly lower than that in non-APAP group (0.5% vs. 2.7%, OR = 0.301; 95% CI, 0.170-0.531; P < 0.001). The APAP group also showed a significant advantage in Cox regression analysis (0.5% vs. 2.7%, HR = 0.329; 95% CI, 0.187-0.577; P < 0.001). IPTW, OW, and PSM analyses were conducted between the two groups, and the differences remained significant. These results were consistent in 30-, 60-, and 90-day mortality analyses. Meanwhile, exposure to APAP was associated with a shorter length of hospital stay and a reduced duration of MV (P < 0.001). CONCLUSION The administration of APAP was associated with reduced early mortality in patients with CABG-ARDS, as well as shorter length of hospital stay and duration of MV.
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Affiliation(s)
- Long Gui
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, Guangdong, 510120, PR China.
- Department of Cardiothoracic Surgery, Lu 'an Hospital Affiliated to Anhui Medical University, 21 Wanxi West Road, Jin'an District, Lu'an, Anhui, 237005, PR China.
| | - Heshan Cao
- Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, PR China
| | - Min Zheng
- Department of Cardiothoracic Surgery, Lu 'an Hospital Affiliated to Anhui Medical University, 21 Wanxi West Road, Jin'an District, Lu'an, Anhui, 237005, PR China
| | - Yu Pan
- Department of Cardiothoracic Surgery, Lu 'an Hospital Affiliated to Anhui Medical University, 21 Wanxi West Road, Jin'an District, Lu'an, Anhui, 237005, PR China
| | - Chengdong Ning
- Department of Cardiothoracic Surgery, Lu 'an Hospital Affiliated to Anhui Medical University, 21 Wanxi West Road, Jin'an District, Lu'an, Anhui, 237005, PR China
| | - Mingjin Cheng
- Department of Cardiothoracic Surgery, Lu 'an Hospital Affiliated to Anhui Medical University, 21 Wanxi West Road, Jin'an District, Lu'an, Anhui, 237005, PR China.
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13
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Ye C, Yu Y, Liu Y. Dexmedetomidine administration reduced mortality in patients with acute respiratory distress syndrome: a propensity score-matched cohort analysis. Front Med (Lausanne) 2025; 12:1565098. [PMID: 40313556 PMCID: PMC12043469 DOI: 10.3389/fmed.2025.1565098] [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: 01/22/2025] [Accepted: 04/07/2025] [Indexed: 05/03/2025] Open
Abstract
Background Acute respiratory distress syndrome (ARDS) continues to pose significant difficulties due to the scarcity of successful preventative and therapeutic measures. Recent clinical trials and experimental research have confirmed the lung-protective and anti-inflammatory properties of dexmedetomidine. The objective of this study was to examine the relationship between the use of dexmedetomidine and mortality outcomes in ICU patients with ARDS. Methods This study retrospectively examined data from the Medical Information Mart for Intensive Care (MIMIC) IV, focusing on individuals diagnosed with ARDS. The primary endpoint was the occurrence of death within 28 days after entering the ICU. To ensure a balanced cohort, we applied propensity score matching at a 1:1 ratio. Additionally, multivariable analysis was performed to mitigate the effects of confounding factors. Results In this study, a cohort comprising 612 patients diagnosed with ARDS was investigated. Analysis using both univariate and multivariate Cox regression indicated significantly reduced 28-day and 90-day mortality rates in patients administered dexmedetomidine compared to those who were not given this treatment. Following adjustments for potential confounders using propensity score matching, these results were confirmed to be robust. Conclusion The results indicate an association between the administration of dexmedetomidine and lower mortality rates among severely ill ARDS patients. However, this result should be interpreted with cause because of a lot of missing data of potential risk factors for clinical outcomes. Nonetheless, it is imperative to perform further randomized controlled trials to corroborate this finding.
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Affiliation(s)
- Conglin Ye
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- The First Clinical Medical College of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Yang Yu
- The First Clinical Medical College of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Yi Liu
- The First Clinical Medical College of Gannan Medical University, Ganzhou, Jiangxi, China
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Jogi S, Shah DK. Effect of Acute Lung Injury (ALI) Induced by Lipopolysaccharide (LPS) on the Pulmonary Pharmacokinetics of an Antibody. Antibodies (Basel) 2025; 14:33. [PMID: 40265414 PMCID: PMC12015819 DOI: 10.3390/antib14020033] [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: 02/21/2025] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/24/2025] Open
Abstract
OBJECTIVE To investigate the effect of Lipopolysaccharide (LPS)-induced acute lung injury (ALI) on the pulmonary pharmacokinetics (PK) of a systemically administered antibody in mice. METHOD The PK of a non-target-binding antibody was evaluated in healthy mice and mice with intratracheal instillation of 5 mg/kg LPS. The plasma, bronchoalveolar lavage (BAL), trachea, bronchi, and lung homogenate PK of the antibody were measured following intravenous administration of 5 mg/kg antibody dose. Noncompartmental analysis was performed to determine AUC values. Antibody concentrations in all biological matrices were quantified using qualified ELISA. The effect of ALI on BAL albumin and total protein concentrations was also determined. BAL protein concentrations were corrected for dilution using plasma urea concentrations. RESULTS Intratracheal instillation of LPS and the resultant ALI led to ~2-4-fold higher concentrations of albumin and proteins in the BAL. LPS-induced ALI also notably altered the pulmonary PK of the antibody. The effect of ALI on the antibody PK was time and tissue dependent. The trachea and bronchi showed ~1.7-fold and ~1.4-fold lower antibody exposure compared with the control group, but the BAL fluid exhibited ~4-fold increase in antibody exposure following LPS treatment. Most noticeable changes in antibody PK occurred 24 h after LPS administration, and the effect was temporary for the bronchi and trachea. However, the changes in lung homogenate and, more notably, in BAL persisted until the end of the experiment. Thus, our investigation suggests that due to the acute nature of ALI-induced pathophysiology and the changing severity of the disease, the dose and timing of antibody administration following ALI may need to be optimized based on the target site of action (e.g., bronchi, trachea, BAL, lung parenchyma, etc.) to maximize the therapeutic effect of the antibody. CONCLUSIONS ALI may significantly affect pulmonary PK of systemically administered antibodies. Changes caused by ALI are time and tissue dependent, and hence, the timing and dose of antibody following ALI may need to be optimized to maximize the therapeutic effect of the antibody at the site of action.
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Affiliation(s)
| | - Dhaval K. Shah
- Department of Pharmaceuticals Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214-8033, USA;
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15
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Grotberg JB, Romanò F, Grotberg JC. Flow mechanisms of the air-blood barrier. PLoS Comput Biol 2025; 21:e1012917. [PMID: 40208907 PMCID: PMC12052194 DOI: 10.1371/journal.pcbi.1012917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 05/05/2025] [Accepted: 02/25/2025] [Indexed: 04/12/2025] Open
Abstract
The air-blood barrier protects the lung from blood/serum entering the air spaces, i.e., from "drowning in your own fluids". Failure leads to pulmonary edema, a regularly fatal complication during the Covid-19 pandemic which claimed 7 million lives worldwide. Finding no mathematical models for the underlying fluid mechanics, we created the first. Governing flow equations for alveolar capillary, interstitium, and alveolus are coupled by crossflows at the capillary and epithelial membranes and end-exit flows to the lymphatics. Case examples include normal/recovery, cardiogenic pulmonary edema, acute respiratory distress syndrome, effects of positive end expiratory pressure, and a wide range of parameter values for permeability of the membranes and interstitial matrix. Previously unknown membrane fluid shear stresses calculate to values that affect cell function in many systems. We add active epithelial reabsorption which has two effects: shifting streamlines to favor alveolar-lymphatic clearance and adding to the direct alveolar-capillary clearance. Simple algebraic equations are derived for the interstitial fluid pressure, pi, membrane crossflow velocities and the critical capillary pressure, pcrit, above which edema occurs. For validation, the pcrit predictions fit clinical definitions and flow calculations of lymphatic vs capillary clearance match animal experimental data. For decades the value of pi has been imposed as an input, whereas we calculate the value as an output. They don't agree. Since the space is too small for measurements, the ability to calculate pi and pcrit offers new insights, questions long-held beliefs, and opens applications from physiological studies to personalized clinical care.
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Affiliation(s)
- James B. Grotberg
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America
| | - Francesco Romanò
- Univ. Lille, CNRS, ONERA, Arts et Métiers Institute of Technology, Centrale Lille, UMR, LMFL - Laboratoire de Mécanique des Fluides de Lille - Kampé de Fériet, Lille, France
| | - John C. Grotberg
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
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16
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Taenaka H, Matthay MA. Mechanisms of impaired alveolar fluid clearance. Anat Rec (Hoboken) 2025; 308:1026-1039. [PMID: 36688689 PMCID: PMC10564110 DOI: 10.1002/ar.25166] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/09/2022] [Accepted: 01/04/2023] [Indexed: 01/24/2023]
Abstract
Impaired alveolar fluid clearance (AFC) is an important cause of alveolar edema fluid accumulation in patients with acute respiratory distress syndrome (ARDS). Alveolar edema leads to insufficient gas exchange and worse clinical outcomes. Thus, it is important to understand the pathophysiology of impaired AFC in order to develop new therapies for ARDS. Over the last few decades, multiple experimental studies have been done to understand the molecular, cellular, and physiological mechanisms that regulate AFC in the normal and the injured lung. This review provides a review of AFC in the normal lung, focuses on the mechanisms of impaired AFC, and then outlines the regulation of AFC. Finally, we summarize ongoing challenges and possible future research that may offer promising therapies for ARDS.
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Affiliation(s)
- Hiroki Taenaka
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California, USA
- Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California, USA
- Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Suita, Japan
| | - Michael A. Matthay
- Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, California, USA
- Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California, USA
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17
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Upadhyay V, Ortega EF, Ramirez Hernandez LA, Alexander M, Kaur G, Trepka K, Rock RR, Shima RT, Cheshire WC, Alipanah-Lechner N, Calfee CS, Matthay MA, Lee JV, Goga A, Jain IH, Turnbaugh PJ. Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.24.645052. [PMID: 40196632 PMCID: PMC11974820 DOI: 10.1101/2025.03.24.645052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Acute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Here, we use a combination of gnotobiotic mice, cell culture experiments, and re-analyses of a large metabolomics dataset from ARDS patients to reveal that gut bacteria impact lung cellular respiration by releasing metabolites that alter mitochondrial activity in lung epithelium. Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species, Bifidobacterium adolescentis, was sufficient to replicate this effect, leading to a significant increase in mitochondrial membrane potential in lung epithelial cells. We then used genome sequencing and mass spectrometry to confirm that B. adolescentis produces L -lactate, which was sufficient to increase mitochondrial activity in lung epithelial cells. Finally, we found that serum lactate was significantly associated with disease severity in patients with ARDS from the Early Assessment of Renal and Lung Injury (EARLI) cohort. Together, these results emphasize the importance of more broadly characterizing the microbial etiology of ARDS and other lung diseases given the ability of gut bacterial metabolites to remotely control lung cellular respiration. Our discovery of a single bacteria-metabolite pair provides a proof-of-concept for systematically testing other microbial metabolites and a mechanistic biomarker that could be pursued in future clinical studies. Furthermore, our work adds to the growing literature linking the microbiome to mitochondrial function, raising intriguing questions as to the bidirectional communication between our endo- and ecto-symbionts.
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18
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Mokra D, Porvaznik I, Mokry J. N-Acetylcysteine in the Treatment of Acute Lung Injury: Perspectives and Limitations. Int J Mol Sci 2025; 26:2657. [PMID: 40141299 PMCID: PMC11942046 DOI: 10.3390/ijms26062657] [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: 02/05/2025] [Revised: 03/03/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
N-acetylcysteine (NAC) can take part in the treatment of chronic respiratory diseases because of the potent mucolytic, antioxidant, and anti-inflammatory effects of NAC. However, less is known about its use in the treatment of acute lung injury. Nowadays, an increasing number of studies indicates that early administration of NAC may reduce markers of oxidative stress and alleviate inflammation in animal models of acute lung injury (ALI) and in patients suffering from distinct forms of acute respiratory distress syndrome (ARDS) or pulmonary infections including community-acquired pneumonia or Coronavirus Disease (COVID)-19. Besides low costs, easy accessibility, low toxicity, and rare side effects, NAC can also be combined with other drugs. This article provides a review of knowledge on the mechanisms of inflammation and oxidative stress in various forms of ALI/ARDS and critically discusses experience with the use of NAC in these disorders. For preparing the review, articles published in the English language from the PubMed database were used.
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Affiliation(s)
- Daniela Mokra
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, SK-03601 Martin, Slovakia
| | - Igor Porvaznik
- Department of Laboratory Medicine, Faculty of Health Sciences, Catholic University in Ružomberok, SK-03401 Ružomberok, Slovakia;
| | - Juraj Mokry
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, SK-03601 Martin, Slovakia;
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19
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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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Ma W, Tang S, Yao P, Zhou T, Niu Q, Liu P, Tang S, Chen Y, Gan L, Cao Y. Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies. Signal Transduct Target Ther 2025; 10:75. [PMID: 40050633 PMCID: PMC11885678 DOI: 10.1038/s41392-025-02127-9] [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: 01/17/2024] [Revised: 12/27/2024] [Accepted: 12/27/2024] [Indexed: 03/09/2025] Open
Abstract
In recent years, the incidence of acute respiratory distress syndrome (ARDS) has been gradually increasing. Despite advances in supportive care, ARDS remains a significant cause of morbidity and mortality in critically ill patients. ARDS is characterized by acute hypoxaemic respiratory failure with diffuse pulmonary inflammation and bilateral edema due to excessive alveolocapillary permeability in patients with non-cardiogenic pulmonary diseases. Over the past seven decades, our understanding of the pathology and clinical characteristics of ARDS has evolved significantly, yet it remains an area of active research and discovery. ARDS is highly heterogeneous, including diverse pathological causes, clinical presentations, and treatment responses, presenting a significant challenge for clinicians and researchers. In this review, we comprehensively discuss the latest advancements in ARDS research, focusing on its heterogeneity, pathophysiological mechanisms, and emerging therapeutic approaches, such as cellular therapy, immunotherapy, and targeted therapy. Moreover, we also examine the pathological characteristics of COVID-19-related ARDS and discuss the corresponding therapeutic approaches. In the face of challenges posed by ARDS heterogeneity, recent advancements offer hope for improved patient outcomes. Further research is essential to translate these findings into effective clinical interventions and personalized treatment approaches for ARDS, ultimately leading to better outcomes for patients suffering from ARDS.
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Affiliation(s)
- Wen Ma
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China
| | - Songling Tang
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Yao
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tingyuan Zhou
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China
| | - Qingsheng Niu
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Liu
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Shiyuan Tang
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Chen
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Gan
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China.
| | - Yu Cao
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China.
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China.
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Liu JX, Zhang YK, Zhan W, Xie JH, Xu QH, Zhang J, Tai X. USP11 promotes autophagy to attenuate LPS-induced oxidative stress in lung epithelial cells by stabilizing FOXO1 levels. Biochem Biophys Res Commun 2025; 751:151368. [PMID: 39908907 DOI: 10.1016/j.bbrc.2025.151368] [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: 10/03/2024] [Revised: 01/09/2025] [Accepted: 01/19/2025] [Indexed: 02/07/2025]
Abstract
BACKGROUND Acute lung injury (ALI) is a critical condition characterized by severe inflammation and oxidative stress, leading to high morbidity and mortality. Despite advances in understanding ALI pathophysiology, effective treatment options remain limited. The increasing global burden of ALI, driven by factors such as infections, trauma, and environmental pollutants, emphasizes the urgent need for new therapeutic strategies. This study investigates the role of ubiquitin-specific protease 11 (USP11) in modulating Forkhead box protein O1 (FOXO1) to promote autophagy and alleviate oxidative stress in lung epithelial cells, which could provide novel insights into ALI therapeutic strategies. MATERIALS AND METHODS Bioinformatics were utilized to analyze the expression pattern of USP11 and FOXO1 in ALI, and their functions were detected based on gain- and loss-of function studies in vitro and in vivo. Besides, the effects of USP11 on FOXO1 stability and autophagy were examined through Western blot, immunofluorescence, and co-immunoprecipitation assays. RESULTS USP11 was found to be significantly downregulated in ALI, and its over-expression stabilized FOXO1, enhancing autophagy in lung epithelial cells. USP11 over-expression reduced oxidative stress and inflammatory cytokine production in vitro and in vivo. These results highlight the protective role of the USP11-FOXO1 axis in mitigating ALI pathophysiology. CONCLUSIONS This study identifies USP11 as a key regulator of FOXO1 and autophagy in ALI. The stabilization of FOXO1 through USP11 represents a promising therapeutic strategy for reducing oxidative stress and inflammation in ALI, warranting further clinical investigation.
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Affiliation(s)
- Jia-Xing Liu
- The First Department of Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Yu-Kai Zhang
- The Department of Trauma Center, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Wei Zhan
- The Third Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Jun-Hao Xie
- The Department of Trauma Center, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Qi-Hong Xu
- The Department of Trauma Center, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Jing Zhang
- The First Department of Thoracic Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Xiang Tai
- The Department of Trauma Center, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China.
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22
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Woods PS, Mutlu GM. Differences in glycolytic metabolism between tissue-resident alveolar macrophages and recruited lung macrophages. Front Immunol 2025; 16:1535796. [PMID: 40092977 PMCID: PMC11906440 DOI: 10.3389/fimmu.2025.1535796] [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: 11/27/2024] [Accepted: 02/13/2025] [Indexed: 03/19/2025] Open
Abstract
Immunometabolism has emerged as a key area of focus in immunology and has the potential to lead to new treatments for immune-related diseases. It is well-established that glycolytic metabolism is essential for adaptation to hypoxia and for macrophage inflammatory function. Macrophages have been shown to upregulate their glycolytic metabolism in response to pathogens and pathogen-associated molecular patterns such as LPS. As a direct link to the external environment, the lungs' distinctive nutrient composition and multiple macrophage subtypes provide a unique opportunity to study macrophage metabolism. This review aims to highlight how the steady-state airway and severely inflamed airway offer divergent environments for macrophage glycolytic metabolism. We describe the differences in glycolytic metabolism between tissue-resident alveolar macrophages, and other lung macrophages at steady-state and during inflammation/injury. We also provide an overview of experimental guidelines on how to assess metabolism at the cellular level using Seahorse-based bioenergetic analysis including a review of pharmacologic agents used to inhibit or activate glycolysis.
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Affiliation(s)
| | - Gökhan M. Mutlu
- Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University
of Chicago, Chicago, IL, United States
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23
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Malik HN, Jabeen A, Ashraf S, Farooq S, Iqbal H, Ul-Haq Z. Identification of effective synthetic molecules against viral-induced cytokine release syndrome using in silico and in vitro approaches. Mol Divers 2025:10.1007/s11030-025-11136-3. [PMID: 39998576 DOI: 10.1007/s11030-025-11136-3] [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: 08/17/2024] [Accepted: 02/12/2025] [Indexed: 02/27/2025]
Abstract
Acute respiratory distress syndrome (ARDS) is the leading cause of mortality in pathogen-mediated lung inflammation. Viral-induced cytokine release syndrome (CRS) has emerged as a global pandemic, characterized by a hyperactive immune response and excessive cytokine production causing irreversible lung injury. This study aimed to evaluate FDA-approved drugs for their potential to target hyperactive immune response and SARS-CoV-2 viral replication simultaneously. Six potential 3-CLpro inhibitors were identified by molecular docking using MOE software, including ebastine (1), orlistat (2), atracurium besylate (3), piperaquine phosphate (4), valsartan (5), and acarbose (6), among which 1-3 binds strongly to the target protein with binding affinity of - 8.22, - 9.12, and - 7.81, kcal/mol, respectively. Additionally, all identified inhibitors except 4 revealed significant anti-viral potential, with a 50-100% reduction in SARS-CoV-2 plaques. Significant attenuation of phagocyte oxidative burst and inflammatory cytokines (IFN-γ, GM-CSF, IL-6, IL-2, IL-1β, TNF-α) demonstrated the immunomodulatory potential of these drugs. This study demonstrates the potential of pre-existing drugs to ameliorate the cytokine storm and oxidative damage with simultaneous anti-viral effects. The data provide pre-clinical support to develop these drugs as potential therapeutic agent against ARDS.
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Affiliation(s)
- Hira Noor Malik
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Almas Jabeen
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
| | - Sajda Ashraf
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Saba Farooq
- National Institute of Virology, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Hana'a Iqbal
- National Institute of Virology, Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Zaheer Ul-Haq
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
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24
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Soltész L, Leyens J, Vogel M, Muders T, Putensen C, Kipfmueller F, Dresbach T, Mueller A, Schroeder L. EIT guided evaluation of regional ventilation distributions in neonatal and pediatric ARDS: a prospective feasibility study. Respir Res 2025; 26:60. [PMID: 39972380 PMCID: PMC11841312 DOI: 10.1186/s12931-025-03134-8] [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: 09/18/2024] [Accepted: 02/01/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Despite international guidelines for lung protective ventilation in neonatal or pediatric acute respiratory distress syndrome (nARDS/ pARDS), prospective data on bedside monitoring tools for regional ventilation distribution and lung mechanics are still rare. As a bedside and radiation-free procedure, electrical impedance tomography (EIT) offers a practical and safe approach for analyzing regional ventilation distributions. Recent trials in adults have shown the efficacy of an individualized EIT guided strategy for the improvement of ventilator induced lung injury (VILI). METHODS We performed a single-center prospective feasibility study from November/2021 to December/2023 in the department of neonatal and pediatric intensive care medicine at the University Children´s Hospital in Bonn. All patients with diagnosis of nARDS (or history of perinatal lung disease-PLD)/ pARDS were screened for study inclusion. In all patients a decremental PEEP (positive end-expiratory pressure) trial was performed with a continuous EIT monitoring for an individual analysis of the EIT guided pixel compliance (CEIT) and PEEP finding (EIT-PEEP). In the offline analysis, further EIT derived indices, such as global inhomogeneity index (GI), and center of ventilation (CoV), were calculated. RESULTS Overall, 40 EIT measurements were performed in 26 neonatal and pediatric patients (nARDS/PLD, n = 6; and pARDS, n = 20) within a predefined decremental PEEP trial. Thirteen patients were classified as having severe nARDS (PLD)/ pARDS with an Oxygen Saturation Index (OSI) > 12 or Oxygenation Index (OI) > 16. In-hospital mortality rate was 27% in the overall cohort. The median EIT-PEEP (11mbar) was calculated as lowest, as compared to the clinically set PEEP (11.5mbar, p < 0.001), and the ARDSnetwork PEEP table recommendation (ARDSnet-PEEP, 14mbar, p = 0.018). In patients with nARDS/PLD, the EIT-PEEP was calculated 3mbar below the clinically set PEEP (p = 0.058) and 11 mbar below the ARDSnet-PEEP (p = 0.01). In the linear regression analysis, EIT-PEEP and the dynamic compliance (CDYN) at -2mbar presented a significant correlation with a Cohen´s R2 of 0.265 (β: 0.886, p = 0.005). CONCLUSION EIT is feasible and can be performed safely in patients with diagnosis of nARDS/PLD and pARDS, even during ongoing extracorporeal membrane oxygenation (ECMO) support. An individualized PEEP finding strategy according to the EIT compliance might optimize regional ventilation distribution in these patients and can potentially decrease VILI. CLINICAL TRIAL REGISTRATION The study was registered at the German Clinical Trials Register (GCT; trial number: DRKS 00034905, Registration Date 15.08.2024). The registration was performed retrospectively after inclusion of the last patient.
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Affiliation(s)
- Leon Soltész
- Department of Neonatology and Pediatric Intensive Care, University Children´s Hospital Bonn, Bonn, Germany
| | - Judith Leyens
- Department of Neonatology and Pediatric Intensive Care, University Children´s Hospital Bonn, Bonn, Germany
- Division of Neonatology, Department of Pediatrics, BC Women's and Children's Hospital, University of British Columbia, Vancouver, Canada
| | - Marieke Vogel
- Division of Neonatology, Department of Pediatric and Adolescent Medicine, University Hospital RWTH Aachen, Aachen, Germany
| | - Thomas Muders
- Department of Anesthesiology and Operative Intensive Care Medicine, University Hospital Bonn, Bonn, Germany
| | - Christian Putensen
- Department of Anesthesiology and Operative Intensive Care Medicine, University Hospital Bonn, Bonn, Germany
| | - Florian Kipfmueller
- Department of Neonatology and Pediatric Intensive Care, University Children´s Hospital Bonn, Bonn, Germany
| | - Till Dresbach
- Department of Neonatology and Pediatric Intensive Care, University Children´s Hospital Bonn, Bonn, Germany
| | - Andreas Mueller
- Department of Neonatology and Pediatric Intensive Care, University Children´s Hospital Bonn, Bonn, Germany
| | - Lukas Schroeder
- Department of Neonatology and Pediatric Intensive Care, University Children´s Hospital Bonn, Bonn, Germany.
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25
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Su E, Song X, Wei L, Xue J, Cheng X, Xie S, Jiang H, Liu M. Endothelial GSDMD underlies LPS-induced systemic vascular injury and lethality. JCI Insight 2025; 10:e182398. [PMID: 39927458 PMCID: PMC11948583 DOI: 10.1172/jci.insight.182398] [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: 04/25/2024] [Accepted: 12/17/2024] [Indexed: 02/11/2025] Open
Abstract
Endothelial injury destroys endothelial barrier integrity, triggering organ dysfunction and ultimately resulting in sepsis-related death. Considerable attention has been focused on identifying effective targets for inhibiting damage to endothelial cells to treat endotoxemia-induced septic shock. Global gasdermin D (Gsdmd) deletion reportedly prevents death caused by endotoxemia. However, the role of endothelial GSDMD in endothelial injury and lethality in lipopolysaccharide-induced (LPS-induced) endotoxemia and the underlying regulatory mechanisms are unknown. Here, we show that LPS increases endothelial GSDMD level in aortas and lung microvessels. We demonstrated that endothelial Gsdmd deficiency, but not myeloid cell Gsdmd deletion, protects against endothelial injury and death in mice with endotoxemia or sepsis. In vivo experiments suggested that hepatocyte GSDMD mediated the release of high-mobility group box 1, which subsequently binds to the receptor for advanced glycation end products in endothelial cells to cause systemic vascular injury, ultimately resulting in acute lung injury and lethality in shock driven by endotoxemia or sepsis. Additionally, inhibiting endothelial GSDMD activation via a polypeptide inhibitor alleviated endothelial damage and improved survival in a mouse model of endotoxemia or sepsis. These data suggest that endothelial GSDMD is a viable pharmaceutical target for treating endotoxemia and endotoxemia-induced sepsis.
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Affiliation(s)
- Enyong Su
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
- Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoyue Song
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Lili Wei
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
- Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Cardiology, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Shanghai, China
| | - Junqiang Xue
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
| | - Xuelin Cheng
- Department of Health Management Center, Zhongshan Hospital, and
- Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shiyao Xie
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hong Jiang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Cardiovascular Diseases, State Key Laboratory of Cardiovascular Diseases, NHC Key Laboratory of Ischemic Heart Diseases, Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, National Clinical Research Center for Interventional Medicine, Shanghai, China
- Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
- Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Fudan University, Shanghai, China
| | - Ming Liu
- Shanghai Engineering Research Center of AI Technology for Cardiopulmonary Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Health Management Center, Zhongshan Hospital, and
- Innovative Center for New Drug Development of Immune Inflammatory Diseases, Ministry of Education, Fudan University, Shanghai, China
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26
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Suárez-Cuenca JA, Flores-Zaleta JF, Corona-Rojas LA, Guzmán-Rullán P, Camacho-Barajas LA, Aguilera-Ontiveros U, Melchor-López A, González-Mora A, Guzmán-Ramírez PM, Rodríguez-Solis J. Tomographic features of lung damage associate with D-Dimer levels and further clinical outcome in patients with acute respiratory distress syndrome due to COVID-19. BMC Pulm Med 2025; 25:65. [PMID: 39915782 PMCID: PMC11800550 DOI: 10.1186/s12890-025-03531-1] [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: 07/18/2024] [Accepted: 01/28/2025] [Indexed: 02/11/2025] Open
Abstract
BACKGROUND Rapid progression of symptoms and development of Acute Respiratory Distress Syndrome (ARDS) frequently occurred during COVID-19 pandemic, while CT-Scan was useful to assess severity of lung damage, with classic patterns like early Ground Glass Opacity and/or late consolidation. Likewise, lung injury has been related to activation of the coagulation-fibrinolysis systems and pro-inflammatory mediators; where D-Dimer acquires prognostic relevance. The present study aimed to evaluate whether the extent of lung involvement and pattern of lung injury, as determined by chest CT-scan, are related with D-Dimer; and further impact clinical prognosis in patients with ARDS due to COVID-19. METHODS Longitudinal, prospective, observational, multi-center study. Patients diagnosed with ARDS due to COVID-19, without previous lung damage, clotting disorder and/or anticoagulants use, who were attended at the Intensive Care Unit and Internal Medicine Department from March to June 2020. Tomographic extent of lung involvement was analyzed by image software, as well as damage patterns, assessed by experienced radiologists. Endpoints included relation of lung injury with coagulopathy markers like D-Dimer, and prognostic outcome including mortality, mechanical ventilation and hospitalization time. RESULTS One-hundred and four patients mean aged 55 years old, 66% males, main comorbidities obesity, hypertension and diabetes mellitus. Larger lung damage was associated with older age, male gender and higher pro-inflammatory mediators like leukocytes and ferritin; whilst consolidation pattern was related to higher Body Mass Index. Higher values of D-Dimer were related either to a larger extent of lung involvement or late consolidation pattern. In addition, the extent of lung involvement was related with longer hospital stay, higher requirement of mechanical ventilation (HR 0.12, p < 0.01) and mortality rate (HR 0.13, p < 0.01); whereas late consolidation was mainly associated with requirement of mechanical ventilation (HR 0.23, p < 0.01). CONCLUSION Tomographic extent of lung involvement and the pattern of lung injury are related with coagulopathy severity markers like D-Dimer, and own prognostic clinical ability in ARDS.
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Affiliation(s)
- Juan Antonio Suárez-Cuenca
- Unidad de Cuidados Intensivos, Corporativo Hospital Satélite. City of State of Mexico, Mexico, Mexico.
- Internal Medicine Department, Hospital General Xoco, SS CDMX, Mexico City, Mexico.
- Naucalpan de Juárez, Circuito Misioneros, No. 5 Colonia Ciudad Satélite, Mexico, CP 53100, State of Mexico, Mexico.
| | | | | | - Pablo Guzmán-Rullán
- Unidad de Cuidados Intensivos, Corporativo Hospital Satélite. City of State of Mexico, Mexico, Mexico
| | | | | | | | - Alejandro González-Mora
- Unidad de Cuidados Intensivos, Corporativo Hospital Satélite. City of State of Mexico, Mexico, Mexico
| | | | - Janicia Rodríguez-Solis
- Unidad de Cuidados Intensivos, Corporativo Hospital Satélite. City of State of Mexico, Mexico, Mexico
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27
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Deng X, He J, Deng W, Deng W, Zhu X, Luo H, Wang D. Celastrol ameliorates lipopolysaccharide (LPS)-induced acute lung injury by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism. Free Radic Biol Med 2025; 227:210-220. [PMID: 39643138 DOI: 10.1016/j.freeradbiomed.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: 09/23/2024] [Revised: 11/16/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
Acute lung injury (ALI) is a devastating clinical syndrome without effective therapy. Celastrol, as a natural anti-inflammatory compound, has showed therapeutic potential against inflammatory diseases. In this study, we have investigated the potential effect of Celastrol on lipopolysaccharide (LPS)-induced ALI. C57BL/6J mice, Nrf1-knockout mice and A549 (human alveolar epithelial cell line) cells were used to investigate the protective role of Celastrol in LPS-induced ALI. Our data showed that administration of Celastrol significantly alleviated lung pathologic injury and increased the survival rate, which was associated with the improvement of mitochondrial function in the injured lung. Moreover, Celastrol enhanced phosphorylation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear translocation of nuclear respiratory factor 1 (Nrf1) and subsequent up-regulation of its downstream mitochondria electron transport chain complex I (NDUF) gene expression, which induced an increase in mitochondrial complex Ⅰ activity. The beneficial effects of Celastrol on regulation of Nrf1 were abolished by inhibition of AMPK and PGC-1α. Finally, in Nrf1 deficient mice, the protective effects of Celastrol on LPS-induced ALI were largely vanished. Our data indicated that Celastrol can prevent LPS-induced ALI by improving mitochondrial function through AMPK/PGC-1α/Nrf1-dependent mechanism, suggesting that Celastrol may represent a novel therapeutic potential for LPS-induced ALI.
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Affiliation(s)
- Xinyu Deng
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing He
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenpeng Deng
- Department of Laboratory and Blood Transfusion of Jiangbei Campus, The First Affiliated Hospital of Army Medical University (The 958th hospital of Chinese People's Liberation Army), Chongqing, China
| | - Wang Deng
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xingyu Zhu
- Faculty of Foresty, University of British Columbia, Vancouver, BC, Canada
| | - Hao Luo
- Department of Cardiology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
| | - Daoxin Wang
- Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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28
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Pathak A, Marshall C, Davis C, Yang P, Kamaleswaran R. RespBERT: A Multi-Site Validation of a Natural Language Processing Algorithm, of Radiology Notes to Identify Acute Respiratory Distress Syndrome (ARDS). IEEE J Biomed Health Inform 2025; 29:1455-1463. [PMID: 40030382 PMCID: PMC11971015 DOI: 10.1109/jbhi.2024.3502575] [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] [Indexed: 04/06/2025]
Abstract
Acute respiratory distress syndrome (ARDS) is a severe organ dysfunction associated with significant mortality and morbidity among critically ill patients admitted to the Intensive Care Unit (ICU). The etiology related to ARDS can be highly heterogeneous, with infection or trauma as the most common associations. The Berlin criteria, the current gold standard for ARDS diagnosis, often necessitates manual adjudication of chest radiographs, limiting automation tools. ARDS diagnosis relies on the presence of bilateral infiltrates on radiographs, which is often not available in Electronic Medical Records (EMRs). Automated identification of radiological evidence would facilitate a comprehensive study of the syndrome, eliminating the need for costly individual image inspections by physicians. Radiological reports enable Natural Language Processing (NLP) to assess lung status and evaluate imaging criteria. We developed a NLP pipeline to analyze radiology notes of 362 patients satisfying sepsis-3 criteria from the EMR for possible ARDS diagnosis using BERT model for classification. These classification models showed F1-score of 74.5% and 64.22% for Emory and Grady dataset respectively.
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Zhu H, Liu L, Yang M, Zhu X, Cai J, Huang H. Nephroblastoma Overexpressed Protein (NOV/CCN3) Elevated Expression of Inflammation Regulators in a Model of Sepsis-Induced Lung Injury. Bull Exp Biol Med 2025; 178:453-459. [PMID: 40156746 DOI: 10.1007/s10517-025-06355-5] [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: 03/15/2023] [Indexed: 04/01/2025]
Abstract
Nephroblastoma overexpressed protein (NOV, also named CCN3), a member of the CCN (Cy61, CTGF, and NOV) family, is a critical biological marker of the severity of acute respiratory distress syndrome (ARDS). However, no evidence has been presented that CCN3 directly affects acute lung injury (ALI) or ARDS. Intratracheal infusion of LPS is an established method to simulate sepsis and induce ALI. To examine the effect of CCN3 on ALI, we developed in vivo and in vitro models of this disease on mice and type II alveolar epithelial A549 cells, respectively. To further clarify the role of CCN3 in ALI, we constructed a CCN3 overexpression model based on plasmid transfection. The results showed that CCN3 expression was up-regulated in LPS-induced ALI both in vivo and in vitro; this effect was time- and dose-dependent. ELISA revealed that overexpression of CCN3 increased the levels of proinflammatory cytokines IL-1β and TNFα. Flow cytometry and Western blotting showed that overexpression of CCN3 increased the expression of proapoptotic protein Bax and decreased the expression of anti-apoptotic protein Bcl-2, thereby promoting apoptosis of A549 cells. The results suggest that CCN3 antagonists can inhibit progression of inflammation and the development of apoptosis in lung epithelial cells, thereby exerting a possible therapeutic effect in ALI.
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Affiliation(s)
- H Zhu
- Department of Intensive Care Unit, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - L Liu
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - M Yang
- Department of Intensive Care Unit, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - X Zhu
- Department of Intensive Care Unit, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - J Cai
- Department of Intensive Care Unit, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - H Huang
- Department of Intensive Care Unit, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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30
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Fioretto JR, Klefens SO, Carpi MF, Moraes MA, Bonatto RC, Ferreira ALA, Corrêa CR, Kurokawa CS, Ronchi CF. Lycopene supplementation reduces inflammatory, histopathological and DNA damage in an acute lung injury rabbit model. CRITICAL CARE SCIENCE 2025; 37:e20250250. [PMID: 39879436 PMCID: PMC11661679 DOI: 10.62675/2965-2774.20250250] [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: 10/20/2023] [Accepted: 03/02/2024] [Indexed: 01/31/2025]
Abstract
OBJECTIVE To investigate the effects of lycopene supplementation on inflammation, lung histopathology and systemic DNA damage in an experimentally induced lung injury model, ventilated by conventional mechanical ventilation and high-frequency oscillatory ventilation, compared with a control group. METHODS Fifty-five rabbits sampled by convenience were supplemented with 10mg/kg lycopene for 21 days prior to the experiment. Lung injury was induced by tracheal infusion of warm saline. The rabbits were randomly assigned to the control group and subjected to protective conventional mechanical ventilation (n = 5) without supplementation or the experimental group that was subjected to acute lung injury and provided conventional mechanical ventilation and high-frequency oscillatory ventilation with and without lycopene supplementation (n = 10 rabbits in each group). Lung oxidative stress and the inflammatory response were assessed based on the number of polymorphonuclear leukocytes in bronchoalveolar lavage fluid, DNA damage and pulmonary histological damage. RESULTS A significant worsening of oxygenation and a decrease in static lung compliance was noted in all groups after pulmonary injury induction (partial pressure of oxygen before 451.86 ± 68.54 and after 71 ± 19.27, p < 0.05). After 4 hours, the high-frequency oscillatory ventilation groups with and without lycopene supplementation as well as the group receiving protective conventional mechanical ventilation with lycopene supplementation showed significant oxygenation improvement compared with the protective conventional mechanical ventilation group without supplementation (partial pressure of oxygen of the group with mechanical ventilation without lycopene of 102 ± 42, of the group that received conventional protective mechanical ventilation with lycopene supplementation of 362 ± 38, of the high-frequency group without lycopene supplementation of 420 ± 28 and of the high-frequency group with lycopene supplementation of 422 ± 25; p < 0.05). Compared with rabbits not receiving supplementation, those in the groups that received protective conventional mechanical ventilation with lycopene supplementation and high-frequency oscillatory ventilation with lycopene supplementation had significantly less inflammation as well as less histological injury (p < 0.05). Compared with rabbits subjected to protective conventional mechanical ventilation, significantly lower DNA damage was observed in rabbits supplemented with lycopene (p < 0.05). CONCLUSION Lycopene supplementation reduces inflammatory and histopathological lung injuries, regardless of the associated ventilatory mode. In addition, lycopene improved oxygenation and reduced DNA damage when protective conventional mechanical ventilation was used.
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Affiliation(s)
- José Roberto Fioretto
- Department of PediatricsFaculdade de Medicina Campus de BotucatuUniversidade Estadual Paulista “Júlio de Mesquita Filho”BotucatuSPBrazilDepartment of Pediatrics, Faculdade de Medicina Campus de Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu (SP), Brazil.
| | - Susiane Oliveira Klefens
- Department of PediatricsFaculdade de Medicina Campus de BotucatuUniversidade Estadual Paulista “Júlio de Mesquita Filho”BotucatuSPBrazilDepartment of Pediatrics, Faculdade de Medicina Campus de Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu (SP), Brazil.
| | - Mário Ferreira Carpi
- Department of PediatricsFaculdade de Medicina Campus de BotucatuUniversidade Estadual Paulista “Júlio de Mesquita Filho”BotucatuSPBrazilDepartment of Pediatrics, Faculdade de Medicina Campus de Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu (SP), Brazil.
| | - Marcos Aurélio Moraes
- Department of PediatricsFaculdade de Medicina Campus de BotucatuUniversidade Estadual Paulista “Júlio de Mesquita Filho”BotucatuSPBrazilDepartment of Pediatrics, Faculdade de Medicina Campus de Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu (SP), Brazil.
| | - Rossano César Bonatto
- Department of PediatricsFaculdade de Medicina Campus de BotucatuUniversidade Estadual Paulista “Júlio de Mesquita Filho”BotucatuSPBrazilDepartment of Pediatrics, Faculdade de Medicina Campus de Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu (SP), Brazil.
| | - Ana Lúcia Anjos Ferreira
- Department of PediatricsFaculdade de Medicina Campus de BotucatuUniversidade Estadual Paulista “Júlio de Mesquita Filho”BotucatuSPBrazilDepartment of Pediatrics, Faculdade de Medicina Campus de Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu (SP), Brazil.
| | - Camila Renata Corrêa
- Department of PediatricsFaculdade de Medicina Campus de BotucatuUniversidade Estadual Paulista “Júlio de Mesquita Filho”BotucatuSPBrazilDepartment of Pediatrics, Faculdade de Medicina Campus de Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu (SP), Brazil.
| | - Cilmery Suemi Kurokawa
- Department of PediatricsFaculdade de Medicina Campus de BotucatuUniversidade Estadual Paulista “Júlio de Mesquita Filho”BotucatuSPBrazilDepartment of Pediatrics, Faculdade de Medicina Campus de Botucatu, Universidade Estadual Paulista “Júlio de Mesquita Filho” - Botucatu (SP), Brazil.
| | - Carlos Fernando Ronchi
- Department of Physical TherapyUniversidade Federal de UberlândiaUberlândiaMGBrazilDepartment of Physical Therapy, Universidade Federal de Uberlândia - Uberlândia (MG), Brazil.
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Bridges JP, Vladar EK, Kurche JS, Krivoi A, Stancil IT, Dobrinskikh E, Hu Y, Sasse SK, Lee JS, Blumhagen RZ, Yang IV, Gerber AN, Peljto AL, Evans CM, Redente EF, Riches DW, Schwartz DA. Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium. J Clin Invest 2025; 135:e183836. [PMID: 39744946 PMCID: PMC11684817 DOI: 10.1172/jci183836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.
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Affiliation(s)
- James P. Bridges
- Department of Medicine, National Jewish Health, Denver, Colorado, USA
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Eszter K. Vladar
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jonathan S. Kurche
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA
| | - Andrei Krivoi
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Ian T. Stancil
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA
| | - Evgenia Dobrinskikh
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Yan Hu
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Sarah K. Sasse
- Department of Medicine, National Jewish Health, Denver, Colorado, USA
| | - Joyce S. Lee
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Rachel Z. Blumhagen
- Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA
| | - Ivana V. Yang
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Anthony N. Gerber
- Department of Medicine, National Jewish Health, Denver, Colorado, USA
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA
| | - Anna L. Peljto
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Christopher M. Evans
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA
| | - Elizabeth F. Redente
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA
| | - David W.H. Riches
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA
- Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - David A. Schwartz
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Ye Y, Yang Q, Wei J, Shen C, Wang H, Zhuang R, Cao Y, Ding Y, Xu H, Xiang S, Mei H, Li Z, Ren X, Zhang C, Xiao J, Zheng S, Li T, Zeng R, Liu H, Lin H, Shang-Guan W, Li M, Jin S, Wang Q. RvD1 improves resident alveolar macrophage self-renewal via the ALX/MAPK14/S100A8/A9 pathway in acute respiratory distress syndrome. J Adv Res 2025; 67:289-299. [PMID: 38237770 PMCID: PMC11725153 DOI: 10.1016/j.jare.2024.01.017] [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: 10/21/2023] [Revised: 12/23/2023] [Accepted: 01/12/2024] [Indexed: 02/24/2024] Open
Abstract
INTRODUCTION Acute respiratory distress syndrome (ARDS) is a pulmonary inflammatory process primarily caused by sepsis. The resolution of inflammation is an active process involving the endogenous biosynthesis of specialized pro-resolving mediators, including resolvin D1 (RvD1). Resident alveolar macrophages (RAMs) maintain pulmonary homeostasis and play a key role in the resolution phase. However, the role of RAMs in promoting the resolution of inflammation by RvD1 is unclear. OBJECTIVES Here, we investigated the mechanisms of RvD1 on regulating RAMs to promote the resolution of ARDS. METHODS Mice were administered lipopolysaccharide and/or Escherichia coli via aerosol inhalation to establish a self-limited ARDS model. Then, RvD1 was administered at the peak inflammatory response. RAMs self-renewal was measured by flow cytometry, RAM phagocytosis was measured by two-photon fluorescence imaging. In addition, plasma was collected from intensive care unit patients on days 0-2, 3-5, and 6-9 to measure RvD1 and S100A8/A9 levels using triple quadrupole/linear ion trap mass spectrometry. RESULTS RAMs were found to play a pivotal role in resolving inflammation during ARDS, and RvD1 enhanced RAM proliferation and phagocytosis, which was abrogated by a lipoxin A4 receptor (ALX, RvD1 receptor) inhibitor. Both primary RAMs transfected with rS100A8/A9 and/or S100A8/A9 siRNA and S100A9-/- mice (also deficient in S100A8 function) showed higher turnover and phagocytic function, indicating that RvD1 exerted its effects on RAMs by inhibiting S100A8/A9 production in the resolution phase. RvD1 reduced S100A8/A9 and its upstream MAPK14 levels in vivo and in vitro. Finally, in the patients, RvD1 levels were lower, but S100A8/A9 levels were higher. CONCLUSIONS We propose that RvD1 improved RAM self-renewal and phagocytosis via the ALX/MAPK14/S100A8/A9 signaling pathway. Plasma RvD1 and S100A8/A9 levels were negatively correlated, and associated with the outcome of sepsis-induced ARDS.
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Affiliation(s)
- Yang Ye
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Qian Yang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Jinling Wei
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Chenxi Shen
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Haixing Wang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Rong Zhuang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Yuan Cao
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Yajun Ding
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Haoran Xu
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Shuyang Xiang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Hongxia Mei
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Zhongwang Li
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Xiya Ren
- Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Chen Zhang
- Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Ji Xiao
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Shengxing Zheng
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Ting Li
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Ruifeng Zeng
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Huacheng Liu
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Han Lin
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Wangning Shang-Guan
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China
| | - Ming Li
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China
| | - Shengwei Jin
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China.
| | - Qian Wang
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China; Key Laboratory of Anesthesiology of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, People's Republic of China.
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Limkul L, Tovichien P. Secondary organizing pneumonia after infection. World J Clin Cases 2024; 12:6877-6882. [PMID: 39726927 PMCID: PMC11531977 DOI: 10.12998/wjcc.v12.i36.6877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/14/2024] [Accepted: 09/25/2024] [Indexed: 10/31/2024] Open
Abstract
This editorial explores the clinical implications of organizing pneumonia (OP) secondary to pulmonary tuberculosis, as presented in a recent case report. OP is a rare condition characterized by inflammation in the alveoli, which spreads to alveolar ducts and terminal bronchioles, usually after lung injuries caused by infections or other factors. OP is classified into cryptogenic (idiopathic) and secondary forms, the latter arising after infections, connective tissue diseases, tumors, or treatments like drugs and radiotherapy. Secondary OP may be triggered by infections caused by bacteria, viruses, fungi, mycobacteria, or parasites. Key diagnostic features include subacute onset of nonspecific respiratory symptoms such as dry cough, chest pain, and exertional dyspnea. Imaging with computed tomography scans typically reveals three patterns: (1) Bilateral subpleural consolidation; (2) Nodular consolidation; and (3) A reticular pattern. Bronchoscopy with bronchoalveolar lavage helps exclude other causes. Standard treatment consists of corticosteroid therapy tapered over 6 months to 12 months. This editorial highlights clinical and diagnostic strategies to ensure timely and effective patient care.
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Affiliation(s)
- Lertluksana Limkul
- Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Prakarn Tovichien
- Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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Millar MW, Najar RA, Slavin SA, Shadab M, Tahir I, Mahamed Z, Lin X, Abe JI, Wright TW, Dean DA, Fazal F, Rahman A. MTOR maintains endothelial cell integrity to limit lung vascular injury. J Biol Chem 2024; 300:107952. [PMID: 39510184 PMCID: PMC11664419 DOI: 10.1016/j.jbc.2024.107952] [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: 02/12/2024] [Revised: 09/21/2024] [Accepted: 10/09/2024] [Indexed: 11/15/2024] Open
Abstract
The functional and structural integrity of the endothelium is essential for vascular homeostasis. Loss of barrier function in quiescent and migratory capacity in proliferative endothelium causes exuberant vascular permeability, a cardinal feature of many inflammatory diseases including acute lung injury (ALI). However, the signals governing these fundamental endothelial cell (EC) functions are poorly understood. Here, we identify mechanistic target of rapamycin (MTOR) as an important link in preserving the barrier integrity and migratory/angiogenic responses in EC and preventing lung vascular injury and mortality in mice. Knockdown of MTOR in EC altered cell morphology, impaired proliferation and migration, and increased endocytosis of cell surface vascular endothelial (VE)-cadherin leading to disrupted barrier function. MTOR-depleted EC also exhibited reduced VE-cadherin and vascular endothelial growth factor receptor-2 (VEGFR2) levels mediated in part by autophagy. Similarly, lungs from mice with EC-specific MTOR deficiency displayed spontaneous vascular leakage marked by decreased VE-cadherin and VEGFR2 levels, indicating that MTOR deficiency in EC is sufficient to disrupt lung vascular integrity and may be a key pathogenic mechanism of ALI. Indeed, MTOR as well as VEGFR2 and VE-cadherin levels were markedly reduced in injured mouse lungs or EC. Importantly, EC-targeted gene transfer of MTOR complementary DNA, either prophylactically or therapeutically, mitigated inflammatory lung injury, and improved lung function and survival in mouse models of ALI. These findings reveal an essential role of MTOR in maintaining EC function, identify loss of endothelial MTOR as a key mechanism of lung vascular injury, and show the therapeutic potential of EC-targeted MTOR expression in combating ALI and mortality in mice.
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Affiliation(s)
- Michelle Warren Millar
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Rauf A Najar
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Spencer A Slavin
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Mohammad Shadab
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Imran Tahir
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Zahra Mahamed
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Xin Lin
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Jun-Ichi Abe
- Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Terry W Wright
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - David A Dean
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Fabeha Fazal
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Arshad Rahman
- Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
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Liu Y, Wang X, Chen Y, Zhou L, Wang Y, Li L, Wang Z, Yang L. Pharmacological mechanisms of traditional Chinese medicine against acute lung injury: From active ingredients to herbal formulae. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:155562. [PMID: 39536423 DOI: 10.1016/j.phymed.2024.155562] [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: 03/09/2023] [Revised: 03/17/2024] [Accepted: 03/21/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the leading causes of acute respiratory failure in many critical diseases and are among the main respiratory diseases with high clinical mortality. The global outbreak of coronavirus disease 2019 (COVID-19) can cause severe ARDS, resulting in a steep rise in the number of patient deaths. Therefore, it is important to explore the pathogenesis of ALI and find effective therapeutic agents. In recent years, thanks to modern biomedical tools, some progress has been made in the application of traditional Chinese medicine (TCM) treatment principles based on syndromic differentiation and holistic concepts in clinical and experimental studies of ALI. More and more TCM effective components and formulae have been verified to have significant curative effects, which have a certain guiding significance for clinical practice. PURPOSE It is hoped to provide reference for the clinical research of ALI/ARDS and provide theoretical basis and technical support for the scientific application of TCM in respiratory related diseases. METHODS We performed a literature survey using traditional books of Chinese medicine and online scientific databases including PubMed, Web of Science, Google Scholar, ScienceDirect, China National Knowledge Infrastructure (CNKI), and others up to January 2023. RESULTS In recent years, thanks to modern biomedical tools, some progress has been made in the application of TCM treatment principles based on syndromic differentiation and holistic concepts in clinical and experimental studies of ALI. This paper mainly reviews the research progress of ALI/ARDS mechanism, the understanding of its etiology and pathogenesis by TCM, and the therapeutic effects of TCM formulae and active ingredients of Chinese medicine. A large number of studies have shown that the effective components and formulae of TCM can prevent or treat ALI/ARDS in vivo and in vitro experiments. CONCLUSION TCM effective components and formulae play an important role in the prevention and treatment of ALI/ARDS through multiple approaches and multiple targets, and provide necessary theoretical support for the further development and utilization of TCM resources.
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Affiliation(s)
- Yamin Liu
- The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xunjiang Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yilin Chen
- The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Limei Zhou
- The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yining Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Linnan Li
- The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Zhengtao Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Li Yang
- The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Li G, Chen D, Gao F, Huang W, Wang J, Li Y, Chen B, Zhong Y, Chen R, Huang M. Efficacy of corticosteroids in patients with acute respiratory distress syndrome: a meta-analysis. Ann Med 2024; 56:2381086. [PMID: 39165240 PMCID: PMC11340212 DOI: 10.1080/07853890.2024.2381086] [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: 05/29/2023] [Revised: 04/04/2024] [Accepted: 04/20/2024] [Indexed: 08/22/2024] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS), are respiratory diseases with high morbidity and mortality. Clinical trials investigating the efficacy of corticosteroids in the treatment of ARDS often yield contradictory results. We hereby conducted a systematic review and meta-analysis to investigate the efficacy of corticosteroids in ARDS management. MATERIALS AND METHODS We conducted a search for randomized clinical trials (RCT) and observational studies that utilized corticosteroids for patients with ARDS in Web of Science, PubMed, and Embase. The primary outcome was mortality. Risk of bias was assessed using Cochrane or NOS scales. Statistical effect size was analyzed using the Mantel-Haenszel method. RESULTS A total of 20 studies, comprising 11 observational studies and 9 RCTs, were eligible for analysis. In RCTs, corticosteroids were associated with a reduction of mortality in ARDS patients (relative risk [RR] = 0.80, 95%CI: 0.71-0.91, p = 0.001). Further subgroup analysis indicated that specific variables, such as low-dose (RR = 0.81; 95%CI: 0.67-0.98; p = 0.034), methylprednisolone (RR = 0.70; 95%CI: 0.49-0.98; p = 0.035), and dexamethasone (RR = 0.82; 95%CI: 0.69-0.98; p = 0.029) were associated with mortality among patients receiving corticosteroids. However, in observational studies, corticosteroids increased the risk of death (RR = 1.16, 95%CI: 1.04-1.29; p = 0.001). Subgroup analysis showed that the use of high-dose corticosteroids was associated with higher patient mortality (RR = 1.20; 95%CI: 1.04-1.38; p = 0.001). CONCLUSIONS The efficacy of corticosteroids on the mortality of ARDS differed by the type and dosage of corticosteroids used, as well as the etiologies. Current data do not support routine use of corticosteroids in ARDS since protective effects were observed in RCTs but increased mortality was found in observational studies. More well designed and large clinical trials are needed to specify the favorable subgroups for corticosteroid therapy.
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Affiliation(s)
- Guowei Li
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dunfan Chen
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Feng Gao
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Huang
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jin Wang
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yonglin Li
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Baijian Chen
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuejia Zhong
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rui Chen
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Manhua Huang
- Emergency Department, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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Ghiasi M, Kheirandish Zarandi P, Dayani A, Salimi A, Shokri E. Potential therapeutic effects and nano-based delivery systems of mesenchymal stem cells and their isolated exosomes to alleviate acute respiratory distress syndrome caused by COVID-19. Regen Ther 2024; 27:319-328. [PMID: 38650667 PMCID: PMC11035022 DOI: 10.1016/j.reth.2024.03.015] [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: 12/09/2023] [Revised: 03/03/2024] [Accepted: 03/15/2024] [Indexed: 04/25/2024] Open
Abstract
The severe respiratory effects of the coronavirus disease 2019 (COVID-19) pandemic have necessitated the immediate development of novel treatments. The majority of COVID-19-related fatalities are due to acute respiratory distress syndrome (ARDS). Consequently, this virus causes massive and aberrant inflammatory conditions, which must be promptly managed. Severe respiratory disorders, notably ARDS and acute lung injury (ALI), may be treated safely and effectively using cell-based treatments, mostly employing mesenchymal stem cells (MSCs). Since the high potential of these cells was identified, a great deal of research has been conducted on their use in regenerative medicine and complementary medicine. Multiple investigations have demonstrated that MSCs and their products, especially exosomes, inhibit inflammation. Exosomes serve a critical function in intercellular communication by transporting molecular cargo from donor cells to receiver cells. MSCs and their derived exosomes (MSCs/MSC-exosomes) may improve lung permeability, microbial and alveolar fluid clearance, and epithelial and endothelial repair, according to recent studies. This review focuses on COVID-19-related ARDS clinical studies involving MSCs/MSC-exosomes. We also investigated the utilization of Nano-delivery strategies for MSCs/MSC-exosomes and anti-inflammatory agents to enhance COVID-19 treatment.
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Affiliation(s)
- Mohsen Ghiasi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Abdolreza Dayani
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ehsan Shokri
- Department of Nanotechnology, Agricultural Biotechnology Research Institute of Iran (ABRII), Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
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Meegan JE, Rizzo AN, Schmidt EP, Bastarache JA. Cellular Mechanisms of Lung Injury: Current Perspectives. Clin Chest Med 2024; 45:821-833. [PMID: 39443000 PMCID: PMC11499619 DOI: 10.1016/j.ccm.2024.08.004] [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] [Indexed: 10/25/2024]
Abstract
The alveolar-capillary barrier includes microvascular endothelial and alveolar epithelial cells and their matrices, and its disruption is a critical driver of lung injury during development of acute respiratory distress syndrome. In this review, we provide an overview of the structure and function of the alveolar-capillary barrier during health and highlight several important signaling mechanisms that underlie endothelial and epithelial injury during critical illness, emphasizing areas with potential for development of therapeutic strategies targeting alveolar-capillary leak. We also emphasize the importance of biomarker and preclinical studies in developing novel therapies and highlight important areas warranting future investigation.
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Affiliation(s)
- Jamie E Meegan
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Alicia N Rizzo
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 148, Boston, MA 02114, USA
| | - Eric P Schmidt
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Bulfinch 148, Boston, MA 02114, USA
| | - Julie A Bastarache
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Feng N, Li Y, Guo F, Song J, Wang L, Li M, Gao K, Wang X, Chu D, Song Y, Wang L. Fibroblast growth factor 10 alleviates LPS-induced acute lung injury by promoting recruited macrophage M2 polarization. Inflammation 2024:10.1007/s10753-024-02158-4. [PMID: 39538090 DOI: 10.1007/s10753-024-02158-4] [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: 02/20/2024] [Revised: 07/03/2024] [Accepted: 09/30/2024] [Indexed: 11/16/2024]
Abstract
Acute lung injury (ALI) is characterized by damage to the alveoli and an overabundance of inflammation. Representing a serious inflammatory condition, ALI lacks a precise treatment approach. Despite the recognized benefit impacts of Fibroblast growth factor-10 (FGF10) on ALI, the underlying mechanisms remain unelucidated. To study the role of FGF10 in ALI, C57BL/6 J mice were intratracheally injected with 5 mg/kg Lipopolysaccharide (LPS) with FGF10 (5 mg/kg) or an equal volume of PBS. Inflammatory factors were quantified in bronchoalveolar lavage fluid (BALF) and plasma using ELISA. RNA sequencing of F4/80+Ly6G- macrophages in BALF explored changes in macrophage phenotype and potential mechanisms. Macrophage polarization in BALF was assessed using qRT-PCR, flow cytometry, and Western blot analysis. In vitro, a Transwell co-culture of mouse lung epithelial cells (MLE12) and bone marrow macrophages (BMDM) validated the role of FGF10 in modulating LPS-induced macrophage phenotypic changes. FGF10 ameliorated LPS-induced ALI by diminishing pro-inflammatory factors (IL-1β, TNF-α, and IL-6) and the neutrophil accumulation in BALF. FGF10 also increased the levels of anti-inflammatory factor IL-10. The FGF10 intervention group exhibited enhanced gene expression of macrophage arginine biosynthesis marker (ARG1), and expression of M2-type marker CD206 in monocytes and macrophages. In addition, phosphorylated STAT3 expression increased in isolated monocyte-derived macrophages. Experiments in vitro confirmed that FGF10 could elevate macrophage M2 marker ARG1 expression through the JAK2/STAT3 pathway. FGF10 ameliorates acute LPS-induced lung injury by modulating the polarization of monocyte-derived macrophages recruited in the alveolar space to the M2 type.
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Affiliation(s)
- Nana Feng
- Department of Respiratory and Critical Medicine, Shanghai Eighth People's Hospital, Shanghai, 200235, China
| | - Yufan Li
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Fengxia Guo
- Department of Respiratory and Critical Medicine, Shanghai Eighth People's Hospital, Shanghai, 200235, China
| | - Juan Song
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lu Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Miao Li
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Kaijing Gao
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiaocen Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Dejie Chu
- Department of Respiratory and Critical Medicine, Shanghai Eighth People's Hospital, Shanghai, 200235, China.
| | - Yuanlin Song
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, 200032, China.
- Shanghai Respiratory Research Institute, Shanghai, 200032, China.
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200032, China.
- Jinshan Hospital of Fudan University, Shanghai, 201508, China.
| | - Linlin Wang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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Yakut S, Gelen V, Kara H, Özkanlar S, Yeşildağ A. Silver Nanoparticles Loaded With Oleuropein Alleviates LPS-Induced Acute Lung Injury by Modulating the TLR4/P2X7 Receptor-Mediated Inflammation and Apoptosis in Rats. ENVIRONMENTAL TOXICOLOGY 2024; 39:4960-4973. [PMID: 38980228 DOI: 10.1002/tox.24369] [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: 03/25/2024] [Revised: 04/30/2024] [Accepted: 05/23/2024] [Indexed: 07/10/2024]
Abstract
Toll-like receptor 4 (TLR-4) ligands were initially shown to be the source of lipopolysaccharide (LPS), a gram-negative bacterium's cell wall immunostimulatory component. Oxidative stress, apoptosis, and inflammation are all potential effects of LPS treatment on the lungs. By triggering oxidative stress and inflammation, these negative effects could be avoided. Robust flavonoid oleuropein (OLE) exhibits anti-inflammatory, antiproliferative, and antioxidative properties. A nanodelivery system could improve its low bioavailability, making it more effective and useful in treating chronic human ailments. This study evaluates the effects of AgNP-loaded OLE on LPS-induced lung injury in rats in terms of TLR4/P2X7 receptor-mediated inflammation and apoptosis. Forty-eight male albino rats were randomly divided into eight groups. Drugs were administered to the groups in the doses specified as follows: Control, LPS (8 mg/kg ip), OLE (50 mg/kg) AgNPs (100 mg/kg), OLE + AgNPs (50 mg/kg), LPS + OLE (oleuropein 50 mg/kg ig + LPS 8 mg/kg ip), LPS + AgNPs (AgNPs 100 mg/kg ig + LPS 8 mg/kg ip), and LPS + OLE + AgNPs (OLE + AgNPs 50 mg/kg + LPS 8 mg/kg ip). After the applications, the rats were decapitated under appropriate conditions, and lung tissues were obtained. Oxidative stress (SOD, MDA, and GSH), and inflammation (IL-6, IL-1β, TNF-α, Nrf2, P2X7R, AKT, and TLR4) parameters were evaluated in the obtained lung tissues. Additionally, histopathology studies were performed on lung tissue samples. The data obtained were evaluated by comparison between groups. Both OLE and OLE + AgNPs showed potential in reducing oxidative stress, inflammation, and apoptosis (p < 0.05). These findings were supported by histopathological analysis, which revealed that tissue damage was reduced in OLE and OLE + AgNPs-treated groups. According to the results, LPS-induced lung injury can be reduced by using nanotechnology and producing OLE + AgNP.
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Affiliation(s)
- Seda Yakut
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Burdur Mehmet Akif Ersoy University, Burdur, Turkey
| | - Volkan Gelen
- Department of Physiology, Faculty of Veterinary Medicine, Kafkas University, Kars, Turkey
| | - Hülya Kara
- Department of Anatomy, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Seçkin Özkanlar
- Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey
| | - Ali Yeşildağ
- Department of Bioengineering, Faculty of Engineering and Architecture, Kafkas University, Kars, Turkey
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Leung G, Middleton EA. The role of platelets and megakaryocytes in sepsis and ARDS. J Physiol 2024; 602:6047-6063. [PMID: 39425883 DOI: 10.1113/jp284879] [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: 03/01/2024] [Accepted: 09/06/2024] [Indexed: 10/21/2024] Open
Abstract
Since the global COVID-19 pandemic, there has been a renewed focus on lung injury during infection. Systemic inflammatory responses such as acute respiratory distress syndrome (ARDS) and sepsis are a leading cause of morbidity and mortality for both adults and children. Improvements in clinical care have improved outcomes but mortality remains ∼40% and significant morbidity persists for those patients with severe disease. Mechanistic studies of the underlying biological processes remain essential to identifying therapeutic targets. Furthermore, methods for identifying the underlying drivers of organ failure are key to treating and preventing tissue injury. In this review, we discuss the contribution of megakaryocytes (MKs) and platelets to the pathogenesis of systemic inflammatory syndromes. We explore the role of MKs and the new identification of extramedullary MKs during sepsis. We describe the alterations in the platelet transcriptome during sepsis. Lastly, we explore platelet function as defined by aggregation, activation and the formation of heterotypic aggregates. Much more work is necessary to explore the contribution of platelets to these heterogenous syndromes, but the foundation of platelets as key contributors to inflammation has been laid.
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Affiliation(s)
- Gabriel Leung
- Division of Pulmonary, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
| | - Elizabeth A Middleton
- Division of Pulmonary, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
- Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA
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Ishioka H, Ghose A, Kingston HW, Plewes K, Leopold SJ, Srinamon K, Charunwatthana P, Ahmed M, Alam AKMS, Tuip-de Boer A, Hossain MA, Dondorp AM, Schultz MJ. The predictive capacity of biomarkers for clinical pulmonary oedema in patients with severe falciparum malaria is low: a prospective observational study. Malar J 2024; 23:320. [PMID: 39448997 PMCID: PMC11515577 DOI: 10.1186/s12936-024-05142-3] [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: 07/08/2024] [Accepted: 10/12/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Pulmonary oedema is a feared and difficult to predict complication of severe malaria that can emerge after start of antimalarial treatment. Proinflammatory mediators are thought to play a central role in its pathogenesis. METHODS An exploratory study was conducted to evaluate the predictive capacity of biomarkers for development of clinical pulmonary oedema in patients with severe falciparum malaria at two hospitals in Bangladesh. Plasma concentrations of interleukin-6 (IL-6), IL-8, tumour necrosis factor (TNF), soluble Receptor of Advanced Glycation End-products (sRAGE), surfactant protein-D (SP-D), club cell secretory protein (CC16), and Krebs von den Lungen-6 (KL-6) on admission were compared with healthy controls. Correlations between these biomarker and plasma lactate and Plasmodium falciparum histidine-rich protein 2 (PfHRP2) levels were evaluated. Receiver Operating Characteristic (ROC) curves were constructed to assess the predictive capacity for clinical pulmonary oedema of the biomarkers of interest. RESULTS Of 106 screened patients with falciparum malaria, 56 were classified as having severe malaria with a mortality rate of 29%. Nine (16%) patients developed clinical pulmonary oedema after admission. Plasma levels of the biomarkers of interest were higher in patients compared to healthy controls. IL-6, IL-8, TNF, sRAGE, and CC16 levels correlated well with plasma PfHRP2 levels (rs = 0.39; P = 0.004, rs = 0.43; P = 0.001, rs = 0.54; P < 0.001, rs = 0.44; P < 0.001, rs = 0.43; P = 0.001, respectively). Furthermore, IL-6 and IL-8 levels correlated well with plasma lactate levels (rs = 0.37; P = 0.005, rs = 0.47; P < 0.001, respectively). None of the biomarkers of interest had predictive capacity for development of clinical pulmonary oedema. CONCLUSIONS IL-6, IL-8, TNF, sRAGE, SP-D, CC16 and KL-6 cannot be used in predicting clinical pulmonary oedema in severe malaria patients.
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Affiliation(s)
- Haruhiko Ishioka
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
- Division of Infectious Diseases, Jichi Medical University Hospital, 3311-1 Yakushiji Shimotsuke-shi, Tochigi, 329-0498, Japan.
| | | | - Hugh W Kingston
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Katherine Plewes
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Stije J Leopold
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Ketsanee Srinamon
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Prakaykaew Charunwatthana
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Maswood Ahmed
- Chittagong Medical College Hospital, Chattogram, Bangladesh
| | | | - Anita Tuip-de Boer
- Department of Intensive Care, Amsterdam University Medical Center, Amsterdam, Netherlands
| | | | - Arjen M Dondorp
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Marcus J Schultz
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Department of Intensive Care, Amsterdam University Medical Center, Amsterdam, Netherlands
- Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
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Gao N, Liu XY, Chen J, Hu TP, Wang Y, Zhang GQ. Menaquinone-4 Alleviates Sepsis-Associated Acute Lung Injury via Activating SIRT3-p53/SLC7A11 Pathway. J Inflamm Res 2024; 17:7675-7685. [PMID: 39469061 PMCID: PMC11514946 DOI: 10.2147/jir.s486984] [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: 08/24/2024] [Accepted: 10/15/2024] [Indexed: 10/30/2024] Open
Abstract
Background Sepsis-associated acute lung injury (SI-ALI) is triggered by various direct or indirect noncardiogenic factors affecting the alveolar epithelium and capillary endothelial cells. Menaquinone-4 (MK-4), a major component of vitamin K, plays a crucial role as an antioxidant by effectively neutralizing reactive oxygen species (ROS) and safeguarding critical biomolecules from oxidative harm within cells. However, the specific mechanisms and clinical implications of MK-4 in SI-ALI are unclear and require further study. Methods Cecal ligation and puncture (CLP) surgery is a commonly used method to induce sepsis in C57BL/6N wild-type mice, and the mice were administered MK-4 at a dosage of 200 mg/kg/day and 3-TYP at 5 mg/kg/day via intraperitoneal injection for 3 days, or erastin (5 mg/kg) 0.5 hours before CLP surgery. The mice were sacrificed 24 hours after CLP surgery, and blood and lung tissue samples were collected. Pathological changes in the lung tissue and oxidative stress levels were detected. The expression levels of Sirt3, acetylated lysine, p53, SLC7A11 ALOX12 and ferroptosis-related proteins were determined. ligation and puncture (CLP). Results In this study, we observed that the lung inflammation was associated with reduced Sirt3 expression and increased acetylated lysine levels. The progression of SI-ALI was mitigated by MK-4 through its role in upregulating Sirt3 expression. MK-4 achieved antioxidant effects by downregulating ROS and inflammatory factor levels. Mechanistically, MK-4 inhibited the p53/SLC7A11 signalling pathway in ferroptosis by inhibiting the acetylation of p53, independent of p53 levels. In addition, MK-4 inhibited ferroptosis independent of GPX4. These findings indicate that MK-4 is a promising novel therapeutic agent for treating SI-ALI and possibly sepsis. Conclusion These experiments revealed that MK-4 acts as a ferroptosis suppressor, increasing the expression of Sirt3, inhibiting the p53/SLC7A11 signalling pathway, and reducing oxidative stress and inflammatory responses, thereby exerting a protective effect against ALI in sepsis.
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Affiliation(s)
- Nan Gao
- China-Japan Friendship Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
| | - Xiao-Yu Liu
- China-Japan Friendship Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
| | - Jie Chen
- China-Japan Friendship Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
| | - Tian-Peng Hu
- China-Japan Friendship Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China
- Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
| | - Yu Wang
- Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
- Graduate School, Capital Medical University, Beijing, 100069, People’s Republic of China
| | - Guo-Qiang Zhang
- Department of Emergency, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China
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Tukhovskaya EA, Palikova YA, Severyukhina MS, Ismailova AM, Palikov VA, Slashcheva GA, Borozdina NA, Mikhaylov ES, Kravchenko IN, Kazakov VA, Kazakova EN, Kalabina EA, Rasskazova EA, Shinelev MV, Rzhevsky DI, Rykov VA, Dyachenko IA, Murashev AN. Comparison of the Results of Modeling Pulmonary Fibrosis in Sprague Dawley Rats by Intratracheal Administration of Bleomycin in the Form of Sulfate and Chloride at a Dose of 3 mg/kg. Pharmaceuticals (Basel) 2024; 17:1360. [PMID: 39459000 PMCID: PMC11510746 DOI: 10.3390/ph17101360] [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: 08/29/2024] [Revised: 10/04/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Intratracheal administration of bleomycin (BLM) to laboratory rodents is a standard, widely used technique used to model pulmonary fibrosis (PF). BLM, as a modeling agent, is produced mainly in the form of two salts-sulfate and chloride. We compared the results of modeling PF in SD rats by intratracheal administration of BLM sulfate and BLM chloride. Methods: Healthy mature male SD rats were used. PF was modeled by intratracheal administration of BLM sulfate and BLM chloride at a dose of 3 mg/kg. The criteria for the development of PF included body weight gain, changes in respiratory parameters, relative lung weight, cellular composition of broncho-alveolar fluid (BALF), histological assessment of the severity of PF with trichrome Masson staining. Results: Intratracheal administration of both BLM salts led to the development of pronounced PF, which was determined by changes in all of the measured parameters relative to control animals. There were no significant differences between the BLM sulfate and BLM chloride groups in body weight gain, hydroxyproline content, and histological evaluation. However, significant differences were identified in the cellular composition of BALF-a significant increase in alveolar macrophages and neutrophils levels in animals treated with BLM sulfate. Conclusions: Intratracheal administration of both BLM salts led to the development of severe PF; however, the inflammatory process in animals receiving BLM sulfate was more pronounced and prolonged than in animals receiving BLM chloride, which in the former, when observed more than 21 days after modeling, can lead to more severe PF.
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Affiliation(s)
- Elena A. Tukhovskaya
- Shemyakin-Ovchinnicov Institute of Bioorganic Chemistry (Branch), Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino 142290, Russia
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Qiu M, Ma K, Zhang J, Zhao Z, Wang S, Wang Q, Xu H. Isoliquiritigenin as a modulator of the Nrf2 signaling pathway: potential therapeutic implications. Front Pharmacol 2024; 15:1395735. [PMID: 39444605 PMCID: PMC11496173 DOI: 10.3389/fphar.2024.1395735] [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: 03/04/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024] Open
Abstract
Nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor responsible for cytoprotection, plays a crucial role in regulating the expression of numerous antioxidant genes, thereby reducing reactive oxygen species (ROS) levels and safeguarding cells against oxidative stress. Extensive research has demonstrated the involvement of Nrf2 in various diseases, prompting the exploration of Nrf2 activation as a potential therapeutic approach for a variety of diseases. Consequently, there has been a surge of interest in investigating the Nrf2 signaling pathway and developing compounds that can modulate its activity. Isoliquiritigenin (ISL) (PubChem CID:638278) exhibits a diverse range of pharmacological activities, including antioxidant, anticancer, and anti-tumor properties. Notably, its robust antioxidant activity has garnered significant attention. Furthermore, ISL has been found to possess therapeutic effects on various diseases, such as diabetes, cardiovascular diseases, kidney diseases, and cancer, through the activation of the Nrf2 pathway. This review aims to evaluate the potential of ISL in modulating the Nrf2 signaling pathway and summarize the role of ISL in diverse diseases prevention and treatment through modulating the Nrf2 signaling pathway.
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Affiliation(s)
- Mangmang Qiu
- School of Basic Medical Sciences, Xi’an Medical University, Xi’an, China
| | - Kang Ma
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China
| | - Junfeng Zhang
- School of Basic Medical Sciences, Xi’an Medical University, Xi’an, China
| | - Zhaohua Zhao
- School of Basic Medical Sciences, Xi’an Medical University, Xi’an, China
| | - Shan Wang
- Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, China
| | - Qing Wang
- Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, China
| | - Hao Xu
- School of Basic Medical Sciences, Xi’an Medical University, Xi’an, China
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46
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Wang J, Peng X, Yuan N, Wang B, Chen S, Wang B, Xie L. Interplay between pulmonary epithelial stem cells and innate immune cells contribute to the repair and regeneration of ALI/ARDS. Transl Res 2024; 272:111-125. [PMID: 38897427 DOI: 10.1016/j.trsl.2024.05.012] [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: 03/26/2024] [Revised: 05/27/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024]
Abstract
Mammalian lung is the important organ for ventilation and exchange of air and blood. Fresh air and venous blood are constantly delivered through the airway and vascular tree to the alveolus. Based on this, the airways and alveolis are persistently exposed to the external environment and are easily suffered from toxins, irritants and pathogens. For example, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common cause of respiratory failure in critical patients, whose typical pathological characters are diffuse epithelial and endothelial damage resulting in excessive accumulation of inflammatory fluid in the alveolar cavity. The supportive treatment is the main current treatment for ALI/ARDS with the lack of targeted effective treatment strategies. However, ALI/ARDS needs more targeted treatment measures. Therefore, it is extremely urgent to understand the cellular and molecular mechanisms that maintain alveolar epithelial barrier and airway integrity. Previous researches have shown that the lung epithelial cells with tissue stem cell function have the ability to repair and regenerate after injury. Also, it is able to regulate the phenotype and function of innate immune cells involving in regeneration of tissue repair. Meanwhile, we emphasize that interaction between the lung epithelial cells and innate immune cells is more supportive to repair and regenerate in the lung epithelium following acute lung injury. We reviewed the recent advances in injury and repair of lung epithelial stem cells and innate immune cells in ALI/ARDS, concentrating on alveolar type 2 cells and alveolar macrophages and their contribution to post-injury repair behavior of ALI/ARDS through the latest potential molecular communication mechanisms. This will help to develop new research strategies and therapeutic targets for ALI/ARDS.
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Affiliation(s)
- Jiang Wang
- College of Pulmonary & Critical Care Medicine, the Eighth Medical Center of Chinese PLA General Hospital, Beijing 100091, China; Medical School of Chinese PLA, Beijing 100853, China
| | - Xinyue Peng
- Fu Xing Hospital, Capital Medical University, Beijing 100038, China
| | - Na Yuan
- Department of Pulmonary & Critical Care Medicine, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Bin Wang
- Department of Thoracic Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Siyu Chen
- Department of Thoracic Surgery, the Sixth Medical Center of Chinese PLA General Hospital, Beijing 100048, China
| | - Bo Wang
- Department of Thoracic Surgery, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
| | - Lixin Xie
- College of Pulmonary & Critical Care Medicine, the Eighth Medical Center of Chinese PLA General Hospital, Beijing 100091, China; Medical School of Chinese PLA, Beijing 100853, China.
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47
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Gao Z, Cheng S, Wittrup E, Gryak J, Najarian K. Learning using privileged information with logistic regression on acute respiratory distress syndrome detection. Artif Intell Med 2024; 156:102947. [PMID: 39208711 DOI: 10.1016/j.artmed.2024.102947] [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: 11/28/2022] [Revised: 07/02/2024] [Accepted: 08/13/2024] [Indexed: 09/04/2024]
Abstract
The advanced learning paradigm, learning using privileged information (LUPI), leverages information in training that is not present at the time of prediction. In this study, we developed privileged logistic regression (PLR) models under the LUPI paradigm to detect acute respiratory distress syndrome (ARDS), with mechanical ventilation variables or chest x-ray image features employed in the privileged domain and electronic health records in the base domain. In model training, the objective of privileged logistic regression was designed to incorporate data from the privileged domain and encourage knowledge transfer across the privileged and base domains. An asymptotic analysis was also performed, yielding sufficient conditions under which the addition of privileged information increases the rate of convergence in the proposed model. Results for ARDS detection show that PLR models achieve better classification performances than logistic regression models trained solely on the base domain, even when privileged information is partially available. Furthermore, PLR models demonstrate performance on par with or superior to state-of-the-art models under the LUPI paradigm. As the proposed models are effective, easy to interpret, and highly explainable, they are ideal for other clinical applications where privileged information is at least partially available.
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Affiliation(s)
- Zijun Gao
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA.
| | - Shuyang Cheng
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA.
| | - Emily Wittrup
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA.
| | - Jonathan Gryak
- Queens College, City University of New York, New York, 11367, NY, USA.
| | - Kayvan Najarian
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, 48109, MI, USA; Michigan Institute for Data Science (MIDAS), University of Michigan, Ann Arbor, 48109, MI, USA; Department of Emergency Medicine, University of Michigan, Ann Arbor, 48109, MI, USA; Max Harry Weil Institute for Critical Care Research and Innovation, University of Michigan, Ann Arbor, 48109, MI, USA; Queens College, City University of New York, New York, 11367, NY, USA.
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48
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Lee SE, Kim IH, Kang YC, Kim Y, Yu SH, Yeo JS, Kwon I, Lim JH, Kim JH, Han K, Kim SH, Kim CH. Mitochondrial transplantation attenuates lipopolysaccharide-induced acute respiratory distress syndrome. BMC Pulm Med 2024; 24:477. [PMID: 39334020 PMCID: PMC11437886 DOI: 10.1186/s12890-024-03304-2] [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: 05/08/2024] [Accepted: 09/23/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND The mitochondria are essential organelles not only providing cellular energy in the form of ATP, but also regulating the inflammatory response and the cell death program. Mitochondrial dysfunction has been associated with various human diseases, including metabolic syndromes as well as inflammatory and neurodegenerative diseases. Acute respiratory distress syndrome (ARDS) is an acute pulmonary disorder characterized by uncontrolled alveolar inflammation, apoptotic lung epithelial/endothelial cells, and pulmonary edema. Despite the high mortality of ARDS, an effective pharmacotherapy to treat this disease has not been established yet. Therefore, identifying a novel targeted therapy for ARDS is important. Recently, exogenous mitochondrial transplantation was reported to be beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transplantation on ARDS in vitro and in vivo. METHODS Mitochondria were isolated from human stem cells. For in vitro efficacy of mitochondrial transplantation on the inflammation and cell death, murine alveolar macrophages MH-S and human pulmonary microvascular endothelial cells HPMECs were exposed to LPS, respectively. The ARDS mice model established by a single intratracheal instillation of LPS was used for in vivo efficacy of intravenously treated mitochondria. RESULTS Our results showed that the mitochondria isolated from human stem cells exhibited an anti-inflammatory effect against alveolar macrophages and an anti-apoptotic effect against the alveolar epithelial cells. Furthermore, intravenous mitochondrial treatment was associated with the attenuation of lung injury in the LPS-induced ARDS mice. CONCLUSION Dual effects of mitochondria on anti-inflammation and anti-apoptosis support the potential of mitochondrial transplantation as a novel therapeutic strategy for ARDS.
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Affiliation(s)
- Seo-Eun Lee
- Paean Biotechnology, Inc. 5 Samil-daero8-gil, Jung-gu, Seoul, 04552, Korea
| | - In-Hyeon Kim
- Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeongeup, 56212, Korea
- College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Young Cheol Kang
- Paean Biotechnology, Inc. 5 Samil-daero8-gil, Jung-gu, Seoul, 04552, Korea
| | - Yujin Kim
- Paean Biotechnology, Inc. 5 Samil-daero8-gil, Jung-gu, Seoul, 04552, Korea
| | - Shin-Hye Yu
- Paean Biotechnology, Inc. 5 Samil-daero8-gil, Jung-gu, Seoul, 04552, Korea
| | - Jeong Seon Yeo
- Paean Biotechnology, Inc. 5 Samil-daero8-gil, Jung-gu, Seoul, 04552, Korea
| | - Iksun Kwon
- Paean Biotechnology, Inc. 5 Samil-daero8-gil, Jung-gu, Seoul, 04552, Korea
| | - Jun Hyeok Lim
- Paean Biotechnology, Inc. 5 Samil-daero8-gil, Jung-gu, Seoul, 04552, Korea
| | - Je-Hein Kim
- Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeongeup, 56212, Korea
| | - Kyuboem Han
- Paean Biotechnology, Inc. 5 Samil-daero8-gil, Jung-gu, Seoul, 04552, Korea
| | - Sung-Hwan Kim
- Jeonbuk Branch Institute, Korea Institute of Toxicology, Jeongeup, 56212, Korea.
| | - Chun-Hyung Kim
- Paean Biotechnology, Inc. 5 Samil-daero8-gil, Jung-gu, Seoul, 04552, Korea.
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49
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Garbis DVO, Fortes TS, Brito JM, Silva LDM, Trovão LDO, Oliveira AS, Alves PCS, Vale AAM, Reis AS, Azevedo-Santos APS, Maciel MCG, Guerra RNM, Abreu AG, Silva LA, Berretta AA, Nascimento FRF. Prophylactic use of standardized extract of propolis of Apis mellifera (EPP-AF®) reduces lung inflammation and improves survival in experimental lethal sepsis. JOURNAL OF ETHNOPHARMACOLOGY 2024; 331:118294. [PMID: 38729541 DOI: 10.1016/j.jep.2024.118294] [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: 03/04/2024] [Revised: 04/22/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Sepsis poses one of the biggest public health problems, necessitating the search for new therapeutic alternatives. For centuries, propolis has been widely used in folk medicine to treat various inflammatory and infectious diseases. Given its extensive use, it has excellent potential as an adjuvant treatment for patients with sepsis. OBJECTIVE This study evaluated prophylactic treatment with standardized propolis extract (EPP-AF®) and followed the prognosis of sepsis induced by ligation and cecal ligation and puncture (CLP). METHODS Initially, for survival assessment, Swiss mice were separated into five groups: Sham (false operated), control (PBS), ATB (received antibiotic, 8 mg/kg), P10 (received EPP-AF®, 10 mg/kg), and P100 (received EPP-AF®, 100 mg/kg). The animals received PBS, antibiotic, or EPP-AF® by the subcutaneous route 6 h before the CLP procedure. Animal survival was assessed every 12 h for five days when all of them were euthanized. RESULTS We show that the treatment with EPP-AF® significantly increased the life expectancy of animals with sepsis compared to the control group. Interestingly, prophylactic treatment with EPP-AF® showed no effect on the number of colony-forming units in the peritoneum, blood, or lung. However, there was a decrease in cellular influx in the peritoneum. This alteration was unrelated to the number of bone marrow cells or the differential counting of peripheral blood cells. The coagulogram remained unchanged, including the number of platelets and prothrombin time-activated partial thromboplastin time. However, the inflammatory infiltrate and bleeding in the lung tissue were lower in the animals that received EPP-AF®. CONCLUSION Thus, it was possible to conclude that prophylactic treatment with EPP-AF® preserved the lung parenchyma, resulting in an increased lifespan of mice with sepsis. It can be a helpful adjuvant in prophylactic treatment with antibiotics in presurgical conditions.
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Affiliation(s)
- Dimitrius V O Garbis
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Imunofisiologia, Universidade Federal do Maranhão, São Luís, Brazil
| | - Thiare S Fortes
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Imunofisiologia, Universidade Federal do Maranhão, São Luís, Brazil
| | - Jefferson M Brito
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Patologia e Imunoparasitologia (LPI), Universidade Federal do Maranhão, São Luís, Maranhão, Brazil
| | - Luis Douglas M Silva
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Patologia e Imunoparasitologia (LPI), Universidade Federal do Maranhão, São Luís, Maranhão, Brazil
| | - Liana de O Trovão
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Aluisio S Oliveira
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Imunofisiologia, Universidade Federal do Maranhão, São Luís, Brazil
| | - Patrícia C S Alves
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Imunofisiologia, Universidade Federal do Maranhão, São Luís, Brazil
| | - André A M Vale
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Imunologia Aplicada ao Câncer (LIAC), Centro de Ciências Biológicas e da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil
| | - Aramys S Reis
- Laboratório de Fisiopatologia e Investigação Terapêutica (LAFIT), Centro de Ciências de Imperatriz, Universidade Federal do Maranhão, Imperatriz, Maranhão, Brazil; Programa de Pós-Graduação em Saúde e Tecnologia, Universidade Federal do Maranhão, Imperatriz, Maranhão, Brazil
| | - Ana Paula S Azevedo-Santos
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Imunologia Aplicada ao Câncer (LIAC), Centro de Ciências Biológicas e da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil
| | - Marcia C G Maciel
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Programa de Pós-Graduação em Saúde e Tecnologia, Universidade Federal do Maranhão, Imperatriz, Maranhão, Brazil; Departmento de Biologia Celular, Universidade de Brasília, Brasília, Distrito Federal, Brazil
| | - Rosane N M Guerra
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Imunofisiologia, Universidade Federal do Maranhão, São Luís, Brazil
| | - Afonso G Abreu
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Programa de Pós-Graduação em Biologia Microbiana, Universidade CEUMA, São Luís, Maranhão, Brazil
| | - Lucilene A Silva
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Patologia e Imunoparasitologia (LPI), Universidade Federal do Maranhão, São Luís, Maranhão, Brazil
| | - Andresa A Berretta
- Laboratório de Pesquisa, Desenvolvimento & Inovação, Apis Flora Indl. Coml. Ltda., Ribeirão Preto, São Paulo, Brazil
| | - Flávia R F Nascimento
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil; Laboratório de Imunofisiologia, Universidade Federal do Maranhão, São Luís, Brazil.
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50
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Chen D, Zhou Z, Kong N, Xu T, Liang J, Xu P, Yao B, Zhang Y, Sun Y, Li Y, Wu B, Yang X, Wang H. Inhalable SPRAY nanoparticles by modular peptide assemblies reverse alveolar inflammation in lethal Gram-negative bacteria infection. SCIENCE ADVANCES 2024; 10:eado1749. [PMID: 39270015 PMCID: PMC11397428 DOI: 10.1126/sciadv.ado1749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 08/08/2024] [Indexed: 09/15/2024]
Abstract
Current pharmacotherapy remains futile in acute alveolar inflammation induced by Gram-negative bacteria (GNB), eliciting consequent respiratory failure. The release of lipid polysaccharides after antibiotic treatment and subsequent progress of proinflammatory cascade highlights the necessity to apply effective inflammation management simultaneously. This work describes modular self-assembling peptides for rapid anti-inflammatory programming (SPRAY) to form nanoparticles targeting macrophage specifically, having anti-inflammation and bactericidal functions synchronously. SPRAY nanoparticles accelerate the self-delivery process in macrophages via lysosomal membrane permeabilization, maintaining anti-inflammatory programming in macrophages with efficacy close to T helper 2 cytokines. By pulmonary deposition, SPRAY nanoparticles effectively suppress inflammatory infiltration and promote alveoli regeneration in murine aseptic acute lung injury. Moreover, SPRAY nanoparticles efficiently eradicate multidrug-resistant GNB in alveoli by disrupting bacterial membrane. The universal molecular design of SPRAY nanoparticles provides a robust and clinically unseen local strategy in reverse acute inflammation featured by a high accumulation of proinflammatory cellularity and drug-resistant bacteria.
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Affiliation(s)
- Dinghao Chen
- Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang Province, China
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Ziao Zhou
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Nan Kong
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Tengyan Xu
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Juan Liang
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Pingping Xu
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Bingpeng Yao
- Departments of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University, School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, China
| | - Yu Zhang
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Ying Sun
- Departments of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University, School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, China
| | - Ying Li
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Bihan Wu
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Xuejiao Yang
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Huaimin Wang
- Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, Department of Chemistry, School of Science, Westlake University, Hangzhou 310030, China
- Westlake Laboratory of Life Sciences and Biomedicine, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
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