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Kim J, Seo D, Yoo SY, Lee HJ, Kim J, Yeom JE, Lee JY, Park W, Hong KS, Lee W. Lung-homing nanoliposomes for early intervention in NETosis and inflammation during acute lung injury. NANO CONVERGENCE 2025; 12:8. [PMID: 39894864 PMCID: PMC11788270 DOI: 10.1186/s40580-025-00475-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 01/07/2025] [Indexed: 02/04/2025]
Abstract
Acute lung injury (ALI) is characterized by severe inflammation in lung tissue, excessive immune response and impaired lung function. In hospitalized high-risk patients and cases of secondary infection due to surgical contamination, it can lead to higher mortality rates and require immediate intervention. Currently, clinical treatments are limited in symptomatic therapy as mechanical ventilation and corticosteroids, having insufficient efficacy in mitigating the cause of progression to severe illness. Here we report a pulmonary targeting lung-homing nanoliposome (LHN) designed to attenuate excessive Neutrophil Extracellular Trap formation (NETosis) through sivelestat and DNase-1, coupled with an anti-inflammatory effect mediated by 25-hydroxycholesterol (25-HC), offering a promising intervention for the acute phase of ALI. Through intratracheal delivery, we intend prompt and constant action within the lungs to effectively prevent excessive NETosis. Isolated neutrophils from blood samples of severe ARDS patients demonstrated significant anti-NETosis effects, as well as reduced proinflammatory cytokine secretion. Furthermore, in a murine model of LPS-induced ALI, we confirmed improvements in lung histopathology, and early respiratory function. Also, attenuation of systemic inflammatory response syndrome (SIRS), with notable reductions in NETosis and neutrophil trafficking was investigated. This presents a targeted therapeutic approach that can be applied in early stages of high-risk patients to prevent severe pulmonary disease progression.
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Affiliation(s)
- Jungbum Kim
- Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Donghyuk Seo
- Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - So-Yeol Yoo
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hye-Jin Lee
- Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Jisun Kim
- Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Ji Eun Yeom
- Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea
| | - Jae-Young Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Wooram Park
- Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
- Department of MetaBioHealth, Institute for Cross-disciplinary Studies, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
| | - Kyung Soo Hong
- Division of Pulmonology and Allergy, Department of Internal Medicine, College of Medicine, Regional Center for Respiratory Diseases, Yeungnam University, Yeungnam University Medical Center, Daegu, 42415, Republic of Korea.
| | - Wonhwa Lee
- Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
- Department of MetaBioHealth, Institute for Cross-disciplinary Studies, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
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Gao H, Yuan Z, Liang H, Liu Y. Integrating UPLC-Q-Orbitrap MS with serum pharmacochemistry network and experimental verification to explore the pharmacological mechanisms of Cynanchi stauntonii rhizoma et radix against sepsis-induced acute lung injury. Front Pharmacol 2024; 15:1261772. [PMID: 38584603 PMCID: PMC10995315 DOI: 10.3389/fphar.2024.1261772] [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: 07/19/2023] [Accepted: 01/03/2024] [Indexed: 04/09/2024] Open
Abstract
Introduction: Patients with sepsis are at an incremental risk of acute lung injury (ALI). Baiqian, also known as Cynanchi stauntonii rhizoma et radix (Csrer), has anti-inflammatory properties and is traditionally used to treat cough and phlegm. This study aimed to demonstrate the multicomponent, multitarget, and multi-pathway regulatory molecular mechanisms of Csrer in treating lipopolysaccharide (LPS)-induced ALI. Methods: The bioactive components of Csrer were identified by ultrahigh-performance liquid chromatography Q-Orbitrap mass spectrometry (UPLC-Q-Orbitrap MS). Active targets predicted from PharmMapper. DrugBank, OMIM, TTD, and GeneCards were used to identify potential targets related to ALI. Intersection genes were identified for Csrer against ALI. The PPI network was analysed to identify prime targets. GO and KEGG analyses were performed. A drug-compound-target-pathway-disease network was constructed. Molecular docking and simulations evaluated the binding free energy between key proteins and active compounds. The protective effect and mechanism of Csrer in ALI were verified using an ALI model in mice. Western blot, Immunohistochemistry and TUNEL staining evaluated the mechanisms of the pulmonary protective effects of Csrer. Results: Forty-six bioactive components, one hundred and ninety-two potential cross-targets against ALI and ten core genes were identified. According to GO and KEGG analyses, the PI3K-Akt, apoptosis and p53 pathways are predominantly involved in the "Csrer-ALI" network. According to molecular docking and dynamics simulations, ten key genes were firmly bound by the principal active components of Csrer. The "Csrer-ALI" network was revealed to be mediated by the p53-mediated apoptosis and inflammatory pathways in animal experiments. Conclusion: Csrer is a reliable source for ALI treatment based on its practical components, potential targets and pathways.
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Affiliation(s)
- Hejun Gao
- Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Ziyi Yuan
- Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Haoxuan Liang
- Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Youtan Liu
- Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
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Duijvelaar E, Gisby J, Peters JE, Bogaard HJ, Aman J. Longitudinal plasma proteomics reveals biomarkers of alveolar-capillary barrier disruption in critically ill COVID-19 patients. Nat Commun 2024; 15:744. [PMID: 38272877 PMCID: PMC10811341 DOI: 10.1038/s41467-024-44986-w] [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: 04/28/2023] [Accepted: 01/11/2024] [Indexed: 01/27/2024] Open
Abstract
The pathobiology of respiratory failure in COVID-19 consists of a complex interplay between viral cytopathic effects and a dysregulated host immune response. In critically ill patients, imatinib treatment demonstrated potential for reducing invasive ventilation duration and mortality. Here, we perform longitudinal profiling of 6385 plasma proteins in 318 hospitalised patients to investigate the biological processes involved in critical COVID-19, and assess the effects of imatinib treatment. Nine proteins measured at hospital admission accurately predict critical illness development. Next to dysregulation of inflammation, critical illness is characterised by pathways involving cellular adhesion, extracellular matrix turnover and tissue remodelling. Imatinib treatment attenuates protein perturbations associated with inflammation and extracellular matrix turnover. These proteomic alterations are contextualised using external pulmonary RNA-sequencing data of deceased COVID-19 patients and imatinib-treated Syrian hamsters. Together, we show that alveolar capillary barrier disruption in critical COVID-19 is reflected in the plasma proteome, and is attenuated with imatinib treatment. This study comprises a secondary analysis of both clinical data and plasma samples derived from a clinical trial that was registered with the EU Clinical Trials Register (EudraCT 2020-001236-10, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001236-10/NL ) and Netherlands Trial Register (NL8491, https://www.trialregister.nl/trial/8491 ).
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Affiliation(s)
- Erik Duijvelaar
- Department of Pulmonary Medicine, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
| | - Jack Gisby
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, London, UK
| | - James E Peters
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, London, UK
| | - Harm Jan Bogaard
- Department of Pulmonary Medicine, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Jurjan Aman
- Department of Pulmonary Medicine, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
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4
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Chudow MB, Condeni MS, Dhar S, Heavner MS, Nei AM, Bissell BD. Current Practice Review in the Management of Acute Respiratory Distress Syndrome. J Pharm Pract 2023; 36:1454-1471. [PMID: 35728076 DOI: 10.1177/08971900221108713] [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: 12/15/2022]
Abstract
Acute respiratory distress syndrome (ARDS) presents as an acute inflammatory lung injury characterized by refractory hypoxemia and non-cardiac pulmonary edema. An estimated 10% of patients in the intensive care unit and 25% of those who are mechanically ventilated are diagnosed with ARDS. Increased awareness is warranted as mortality rates remain high and delays in diagnosing ARDS are common. The COVID-19 pandemic highlights the importance of understanding ARDS management. Treatment of ARDS can be challenging due to the complexity of the disease state and conflicting existing evidence. Therefore, it is imperative that pharmacists understand both pharmacologic and non-pharmacologic treatment strategies to optimize patient care. This narrative review provides a critical evaluation of current literature describing management practices for ARDS. A review of treatment modalities and supportive care strategies will be presented.
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Affiliation(s)
- Melissa B Chudow
- Department of Pharmacotherapeutics and Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL, USA
| | - Melanie S Condeni
- MUSC College of Pharmacy, Medical University of South Carolina, Charleston, SC, USA
| | - Sanjay Dhar
- Pulmonary Critical Care Ultrasound and Research, Pulmonary and Critical Care Fellowship Program, Division of Pulmonary, Critical Care & Sleep Medicine, University of Kentucky, Lexington, KY, USA
| | - Mojdeh S Heavner
- Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, MD, USA
| | - Andrea M Nei
- Mayo Clinic College of Medicine & Science, Critical Care Pharmacist, Department of Pharmacy, Mayo Clinic Hospital, Rochester, MN, USA
| | - Brittany D Bissell
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY, USA
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Li H, Li Y, Fu Y, Zhang X, Zhang D. The intensity of organ support: Restrictive or aggressive therapy for critically ill patients. JOURNAL OF INTENSIVE MEDICINE 2023; 3:298-302. [PMID: 38028644 PMCID: PMC10658039 DOI: 10.1016/j.jointm.2023.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/03/2023] [Accepted: 04/20/2023] [Indexed: 12/01/2023]
Abstract
The intensity of organ support has received attention in recent years. To make better clinical decisions, we should understand the mechanisms and benefits, and disadvantages of the different intensities of organ support in critically ill patients. Therapeutic strategies such as supplemental oxygen therapy, mechanical ventilation, respiratory stimulant, vasoactive agents, transfusion, albumin infusion, fluid management, renal placement, and nutrition support, if they are implemented in accordance with an aggressive strategy, could result in side effects and/or complications, resulting in iatrogenic harm in critically ill patients. It is found that the intensity of organ support is not a determining factor in prognosis. A normal rather than supernormal physiological target is recommended for support therapy.
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Affiliation(s)
- Hongxiang Li
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Yuting Li
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Yao Fu
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Xinyu Zhang
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Dong Zhang
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin, China
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6
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Feng F, Wang LJ, Li JC, Chen TT, Liu L. Role of heparanase in ARDS through autophagy and exosome pathway (review). Front Pharmacol 2023; 14:1200782. [PMID: 37361227 PMCID: PMC10285077 DOI: 10.3389/fphar.2023.1200782] [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: 04/05/2023] [Accepted: 05/30/2023] [Indexed: 06/28/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is the most common respiratory disease in ICU. Although there are many treatment and support methods, the mortality rate is still high. The main pathological feature of ARDS is the damage of pulmonary microvascular endothelium and alveolar epithelium caused by inflammatory reaction, which may lead to coagulation system disorder and pulmonary fibrosis. Heparanase (HPA) plays an significant role in inflammation, coagulation, fibrosis. It is reported that HPA degrades a large amount of HS in ARDS, leading to the damage of endothelial glycocalyx and inflammatory factors are released in large quantities. HPA can aggrandize the release of exosomes through syndecan-syntenin-Alix pathway, leading to a series of pathological reactions; at the same time, HPA can cause abnormal expression of autophagy. Therefore, we speculate that HPA promotes the occurrence and development of ARDS through exosomes and autophagy, which leads to a large amount of release of inflammatory factors, coagulation disorder and pulmonary fibrosis. This article mainly describes the mechanism of HPA on ARDS.
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Affiliation(s)
- Fei Feng
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Lin-Jun Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Jian-Chun Li
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Ting-Ting Chen
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Liping Liu
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
- Departments of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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Jia Y, Ren S, Song L, Wang S, Han W, Li J, Yu Y, Ma B. PGLYRP1-mIgG2a-Fc inhibits macrophage activation via AKT/NF-κB signaling and protects against fatal lung injury during bacterial infection. iScience 2023; 26:106653. [PMID: 37113764 PMCID: PMC10102533 DOI: 10.1016/j.isci.2023.106653] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 02/27/2023] [Accepted: 04/07/2023] [Indexed: 04/29/2023] Open
Abstract
Severe bacterial pneumonia leads to acute respiratory distress syndrome (ARDS), with a high incidence rate and mortality. It is well-known that continuous and dysregulated macrophage activation is vital for aggravating the progression of pneumonia. Here, we designed and produced an antibody-like molecule, peptidoglycan recognition protein 1-mIgG2a-Fc (PGLYRP1-Fc). PGLYRP1 was fused to the Fc region of mouse IgG2a with high binding to macrophages. We demonstrated that PGLYRP1-Fc ameliorated lung injury and inflammation in ARDS, without affecting bacterial clearance. Besides, PGLYRP1-Fc reduced AKT/nuclear factor kappa-B (NF-κB) activation via the Fc segment bound Fc gamma receptor (FcγR)-dependent mechanism, making macrophage unresponsive, and immediately suppressed proinflammatory response upon bacteria or lipopolysaccharide (LPS) stimulus in turn. These results confirm that PGLYRP1-Fc protects against ARDS by promoting host tolerance with reduced inflammatory response and tissue damage, irrespective of the host's pathogen burden, and provide a promising therapeutic strategy for bacterial infection.
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Affiliation(s)
- Yan Jia
- Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
| | - Shan Ren
- Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Minhang District, Shanghai 200000, China
| | - Luyao Song
- Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
| | - Siyi Wang
- Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
| | - Wei Han
- Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
| | - Jingjing Li
- Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
| | - Yan Yu
- Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Minhang District, Shanghai 200000, China
| | - BuYong Ma
- Engineering Research Center of Cell & Therapeutic Antibody (MOE), School of Pharmacy, Shanghai Jiao Tong University, Minhang, Shanghai 200000, China
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8
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Kuo CW, Su PL, Huang TH, Lin CC, Chen CW, Tsai JS, Liao XM, Chan TY, Shieh CC. Cigarette smoke increases susceptibility of alveolar macrophages to SARS-CoV-2 infection through inducing reactive oxygen species-upregulated angiotensin-converting enzyme 2 expression. Sci Rep 2023; 13:7894. [PMID: 37193781 DOI: 10.1038/s41598-023-34785-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/08/2023] [Indexed: 05/18/2023] Open
Abstract
Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical-regulatory factors for the entrance protein of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman's r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (β-coefficient: 0.791, 95% CI 0.019-1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb-/- mice; however, exogenous ROS increased the ACE2 in Cybb-/- AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS-induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.
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Affiliation(s)
- Chin-Wei Kuo
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Lan Su
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tang-Hsiu Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chien-Chung Lin
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chian-Wei Chen
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jeng-Shiuan Tsai
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Xin-Min Liao
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Tzu-Yi Chan
- Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Chang Shieh
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan.
- Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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Ma Y, Xu H, Chen G, Liu W, Ma C, Meng J, Yuan L, Hua X, Ge G, Lei M. Uncovering the active constituents and mechanisms of Rujin Jiedu powder for ameliorating LPS-induced acute lung injury using network pharmacology and experimental investigations. Front Pharmacol 2023; 14:1186699. [PMID: 37251341 PMCID: PMC10210165 DOI: 10.3389/fphar.2023.1186699] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/02/2023] [Indexed: 05/31/2023] Open
Abstract
Background: Acute lung injury (ALI) is a common clinical disease with high mortality. Rujin Jiedu powder (RJJD) has been clinically utilized for the treatment of ALI in China, but the active constituents in RJJD and its protective mechanisms against ALI are still unclear. Methodology: ALI mice were established by intraperitoneal injection of LPS to test the effectiveness of RJJD in treating ALI. Histopathologic analysis was used to assess the extent of lung injury. An MPO (myeloperoxidase) activity assay was used to evaluate neutrophil infiltration. Network pharmacology was used to explore the potential targets of RJJD against ALI. Immunohistochemistry and TUNEL staining were performed to detect apoptotic cells in lung tissues. RAW264.7 and BEAS-2B cells were used to explore the protective mechanisms of RJJD and its components on ALI in vitro. The inflammatory factors (TNF-α, IL-6, IL-1β and IL-18) in serum, BALF and cell supernatant were assayed using ELISA. Western blotting was performed to detect apoptosis-related markers in lung tissues and BEAS-2B cells. Results: RJJD ameliorated pathological injury and neutrophil infiltration in the lungs of ALI mice and decreased the levels of inflammatory factors in serum and BALF. Network pharmacology investigations suggested that RJJD treated ALI via regulating apoptotic signaling pathways, with AKT1 and CASP3 as crucial targets and PI3K-AKT signaling as the main pathway. Meanwhile, baicalein, daidzein, quercetin and luteolin were identified as key constituents in RJJD targeting on the above crucial targets. Experimental investigations showed that RJJD significantly upregulated the expression of p-PI3K, p-Akt and Bcl-2, downregulated the expression of Bax, caspase-3 and caspase-9 in ALI mice, and attenuated lung tissue apoptosis. Four active constituents in RJJD (baicalein, daidzein, quercetin and luteolin) inhibited the secretion of TNF-α and IL-6 in LPS-induced RAW264.7 cells. Among these components, daidzein and luteolin activated the PI3K-AKT pathway and downregulated the expression of apoptosis-related markers induced by LPS in BEAS-2B cells. Conclusion: RJJD alleviates the inflammatory storm and prevents apoptosis in the lungs of ALI mice. The mechanism of RJJD in treating ALI is related to the activation of PI3K-AKT signaling pathway. This study provides a scientific basis for the clinical application of RJJD.
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Affiliation(s)
- Yuhui Ma
- Department of Critical Care Medicine, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hong Xu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Gang Chen
- Department of Critical Care Medicine, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Department of Pharmacy, The SATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chao Ma
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jialei Meng
- Department of Critical Care Medicine, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lin Yuan
- Department of Critical Care Medicine, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xu Hua
- Department of Critical Care Medicine, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangbo Ge
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ming Lei
- Department of Critical Care Medicine, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Kuperminc E, Heming N, Carlos M, Annane D. Corticosteroids in ARDS. J Clin Med 2023; 12:jcm12093340. [PMID: 37176780 PMCID: PMC10179626 DOI: 10.3390/jcm12093340] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/04/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is frequently associated with sepsis. ARDS and sepsis exhibit a common pathobiology, namely excessive inflammation. Corticosteroids are powerful anti-inflammatory agents that are routinely used in septic shock and in oxygen-dependent SARS-CoV-2 related acute respiratory failure. Recently, corticosteroids were found to reduce mortality in severe community-acquired pneumonia. Corticosteroids may therefore also have a role to play in the treatment of ARDS. This narrative review was undertaken following a PubMed search for English language reports published before January 2023 using the terms acute respiratory distress syndrome, sepsis and steroids. Additional reports were identified by examining the reference lists of selected articles and based on personnel knowledge of the authors of the field. High-quality research is needed to fully understand the role of corticosteroids in the treatment of ARDS and to determine the optimal timing, dosing and duration of treatment.
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Affiliation(s)
- Emmanuelle Kuperminc
- Department of Intensive Care, Hôpital Raymond Poincaré, APHP University Versailles Saint Quentin-University Paris Saclay, 92380 Garches, France
| | - Nicholas Heming
- Department of Intensive Care, Hôpital Raymond Poincaré, APHP University Versailles Saint Quentin-University Paris Saclay, 92380 Garches, France
- Laboratory of Infection & Inflammation-U1173, School of Medicine Simone Veil, University Versailles Saint Quentin-University Paris Saclay, INSERM, 92380 Garches, France
- FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis), 92380 Garches, France
| | - Miguel Carlos
- Department of Intensive Care, Hôpital Raymond Poincaré, APHP University Versailles Saint Quentin-University Paris Saclay, 92380 Garches, France
| | - Djillali Annane
- Department of Intensive Care, Hôpital Raymond Poincaré, APHP University Versailles Saint Quentin-University Paris Saclay, 92380 Garches, France
- Laboratory of Infection & Inflammation-U1173, School of Medicine Simone Veil, University Versailles Saint Quentin-University Paris Saclay, INSERM, 92380 Garches, France
- FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis), 92380 Garches, France
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11
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Balykova LA, Radaeva OA, Zaslavskaya KY, Bely PA, Pavelkina VF, Pyataev NA, Ivanova AY, Rodoman GV, Kostina NE, Filimonov VB, Simakina EN, Bystritsky DA, Agafyina AS, Koryanova KN, Pushkar DY. EFFICACY AND SAFETY OF ORIGINAL DRUG BASED ON HEXAPEPTIDE SUCCINATE IN COMPLEX COVID-19 THERAPY IN ADULTS HOSPITALIZED PATIENTS. PHARMACY & PHARMACOLOGY 2023. [DOI: 10.19163/2307-9266-2022-10-6-573-588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
Currently, there are data that that make it possible to speak about a high clinical efficacy of the use of succinic salt of tyrosyl-D-alanyl-glycyl-phenylalanyl-leucyl-arginine (hexapeptide succinate) for the COVID-19 treatment. This article is devoted to the results of clinical trials of the original Russian drug based on it.The aim of the study was to evaluate a clinical efficacy, safety and tolerability of intramuscular and inhalation use of hexapeptide succinate in complex therapy in comparison with standard therapy in patients with moderate COVID-19.Materials and methods. The research was conducted from February 28, 2022 to November 22, 2022 based on 10 research centers in the Russian Federation. The study included hospitalized patients (n=312) over 18 years of age with moderate COVID-19 who had undergone a screening procedure and were randomized into 3 groups: group 1 received standard therapy in accordance with the Interim Guidelines in force at the time of the study, within 10 days; group 2 received hexapeptide succinate (Ambervin® Pulmo) intramuscularly at the dose of 1 mg once a day for 10 days; group 3 received hexapeptide succinate (Ambervin® Pulmo) 10 mg once a day by inhalation for 10 days.Results. According to the results of the study, therapy with the drug hexapeptide succinate, both intramuscular and inhaled, provided an acceleration of recovery up to the complete absence of the disease signs in more than 80% of hospitalized COVID-19 patients. By the end of the therapy course with the drug, more than 60% of patients had met the criteria for discharge from hospital and could continue the treatment on an outpatient basis. About 70% of patients in the inhalation group and 80% in the intramuscular hexapeptide succinate injection group had concomitant diseases (hypertension – 28%, obesity – 14%), which indicates the effectiveness of this drug use in comorbid patients. The use of the drug contributed to the restoration of damaged lung tissues, normalization of oxygenation, the disappearance of shortness of breath and a decrease in the duration of the disease symptoms compared with standard therapy. As a result of a comparative analysis of adverse events in terms of their presence, severity, causal relationship with the therapy and outcome, there were no statistically significant differences between the treatment groups.Conclusion. Thus, the results of the clinical study of the succinate hexapeptide efficacy and safety showed the feasibility of using the drug in pathogenetic therapy COVID-19 regimens.
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Affiliation(s)
| | | | | | - P. A. Bely
- Moscow State Medical and Dental University named after A.I. Evdokimov
| | | | | | - A. Yu. Ivanova
- Regional Clinical Hospital;
Ryazan State Medical University named after academician I.P. Pavlov
| | - G. V. Rodoman
- Municipal clinical hospital No. 24, Moscow City Health Department
| | | | - V. B. Filimonov
- Ryazan State Medical University named after academician I.P. Pavlov
| | | | - D. A. Bystritsky
- Infectious Clinical Hospital No. 1, Moscow City Health Department
| | | | - K. N. Koryanova
- Pyatigorsk Medical and Pharmaceutical Institute – branch of Volgograd State Medical University
| | - D. Yu. Pushkar
- Moscow State Medical and Dental University named after A.I. Evdokimov;
City Clinical Hospital named after S.I. Spasokukotsky, Moscow City Health Department
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12
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Mao X, Tretter V, Zhu Y, Kraft F, Vigl B, Poglitsch M, Ullrich R, Abraham D, Krenn K. Combined angiotensin-converting enzyme and aminopeptidase inhibition for treatment of experimental ventilator-induced lung injury in mice. Front Physiol 2023; 14:1109452. [PMID: 37064885 PMCID: PMC10097933 DOI: 10.3389/fphys.2023.1109452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 03/16/2023] [Indexed: 04/18/2023] Open
Abstract
Introduction: Ventilator-induced lung injury (VILI) may aggravate critical illness. Although angiotensin-converting enzyme (ACE) inhibition has beneficial effects in ventilator-induced lung injury, its clinical application is impeded by concomitant hypotension. We hypothesized that the aminopeptidase inhibitor ALT-00 may oppose the hypotension induced by an angiotensin-converting enzyme inhibitor, and that this combination would activate the alternative renin-angiotensin system (RAS) axis to counteract ventilator-induced lung injury. Methods: In separate experiments, C57BL/6 mice were mechanically ventilated with low (LVT, 6 mL/kg) and high tidal volumes (HVT, 30 mL/kg) for 4 h or remained unventilated (sham). High tidal volume-ventilated mice were treated with lisinopril (0.15 μg/kg/min) ± ALT-00 at 2.7, 10 or 100 μg/kg/min. Blood pressure was recorded at baseline and after 4 h. Lung histology was evaluated for ventilator-induced lung injury and the angiotensin (Ang) metabolite profile in plasma (equilibrium levels of Ang I, Ang II, Ang III, Ang IV, Ang 1-7, and Ang 1-5) was measured with liquid chromatography tandem mass spectrometry at the end of the experiment. Angiotensin concentration-based markers for renin, angiotensin-converting enzyme and alternative renin-angiotensin system activities were calculated. Results: High tidal volume-ventilated mice treated with lisinopril showed a significant drop in the mean arterial pressure at 4 h compared to baseline, which was prevented by adding ALT-00 at 10 and 100 μg/kg/min. Ang I, Ang II and Ang 1-7 plasma equilibrium levels were elevated in the high tidal volumes group versus the sham group. Lisinopril reduced Ang II and slightly increased Ang I and Ang 1-7 levels versus the untreated high tidal volumes group. Adding ALT-00 at 10 and 100 μg/kg/min increased Ang I and Ang 1-7 levels versus the high tidal volume group, and partly prevented the downregulation of Ang II levels caused by lisinopril. The histological lung injury score was higher in the high tidal volume group versus the sham and low tidal volume groups, and was attenuated by lisinopril ± ALT-00 at all dose levels. Conclusion: Combined angiotensin-converting enzyme plus aminopeptidase inhibition prevented systemic hypotension and maintained the protective effect of lisinopril. In this study, a combination of lisinopril and ALT-00 at 10 μg/kg/min appeared to be the optimal approach, which may represent a promising strategy to counteract ventilator-induced lung injury that merits further exploration.
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Affiliation(s)
- Xinjun Mao
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
- Department of Anesthesiology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Verena Tretter
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - Yi Zhu
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
- Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Felix Kraft
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | | | | | - Roman Ullrich
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
- Department of Anesthesiology and Intensive Care Medicine, AUVA Trauma Center Vienna, Vienna, Austria
- *Correspondence: Roman Ullrich,
| | - Dietmar Abraham
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Katharina Krenn
- Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria
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13
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He H, Yang W, Su N, Zhang C, Dai J, Han F, Singhal M, Bai W, Zhu X, Zhu J, Liu Z, Xia W, Liu X, Zhang C, Jiang K, Huang W, Chen D, Wang Z, He X, Kirchhoff F, Li Z, Liu C, Huan J, Wang X, Wei W, Wang J, Augustin HG, Hu J. Activating NO-sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury. J Exp Med 2022; 220:213673. [PMID: 36350314 PMCID: PMC9984546 DOI: 10.1084/jem.20211422] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/20/2022] [Accepted: 10/27/2022] [Indexed: 11/11/2022] Open
Abstract
Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC-pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elusive. Using comparative genome-wide EC-pericyte crosstalk analysis of healthy and LPS-challenged lungs, we discovered that crosstalk between endothelial nitric oxide and pericyte soluble guanylate cyclase (NO-sGC) is impaired in ALI. Indeed, stimulating the NO-sGC pathway promotes vascular integrity and reduces lung edema and inflammation-induced lung injury, while pericyte-specific sGC knockout abolishes this protective effect. Mechanistically, sGC activation suppresses cytoskeleton rearrangement in pericytes through inhibiting VASP-dependent F-actin formation and MRTFA/SRF-dependent de novo synthesis of genes associated with cytoskeleton rearrangement, thereby leading to the stabilization of EC-pericyte interactions. Collectively, our data demonstrate that impaired NO-sGC crosstalk in the vascular niche results in elevated vascular permeability, and pharmacological activation of this crosstalk represents a promising translational therapy for ALI.
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Affiliation(s)
- Hao He
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Wu Yang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Nan Su
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Chuankai Zhang
- Department of Burn and Plastic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianing Dai
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Feng Han
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Mahak Singhal
- Laboratory of AngioRhythms, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Wenjuan Bai
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaolan Zhu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Jing Zhu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Zhen Liu
- University of Chinese Academy of Sciences, Beijing, China,Chinese Academy of Sciences Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Wencheng Xia
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoting Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Chonghe Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Kai Jiang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Wenhui Huang
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, Germany
| | - Dan Chen
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Zhaoyin Wang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Xueyang He
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Frank Kirchhoff
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, Germany
| | - Zhenyu Li
- Texas A&M Health Science Center, Bryan, TX
| | - Cong Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China
| | - Jingning Huan
- Department of Burn and Plastic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaohong Wang
- Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Wu Wei
- University of Chinese Academy of Sciences, Beijing, China,Chinese Academy of Sciences Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Jing Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hellmut G. Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany,Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Junhao Hu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,University of Chinese Academy of Sciences, Beijing, China,Correspondence to Junhao Hu:
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14
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COVID-19-Related ARDS: Key Mechanistic Features and Treatments. J Clin Med 2022; 11:jcm11164896. [PMID: 36013135 PMCID: PMC9410336 DOI: 10.3390/jcm11164896] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/15/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome historically characterized by the presence of severe hypoxemia, high-permeability pulmonary edema manifesting as diffuse alveolar infiltrate on chest radiograph, and reduced compliance of the integrated respiratory system as a result of widespread compressive atelectasis and fluid-filled alveoli. Coronavirus disease 19 (COVID-19)-associated ARDS (C-ARDS) is a novel etiology caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may present with distinct clinical features as a result of the viral pathobiology unique to SARS-CoV-2. In particular, severe injury to the pulmonary vascular endothelium, accompanied by the presence of diffuse microthrombi in the pulmonary microcirculation, can lead to a clinical presentation in which the severity of impaired gas exchange becomes uncoupled from lung capacity and respiratory mechanics. The purpose of this review is to highlight the key mechanistic features of C-ARDS and to discuss the implications these features have on its treatment. In some patients with C-ARDS, rigid adherence to guidelines derived from clinical trials in the pre-COVID era may not be appropriate.
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15
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Wang S, Liu J, Dong J, Fan Z, Wang F, Wu P, Li X, Kou R, Chen F. Allyl methyl trisulfide protected against LPS-induced acute lung injury in mice via inhibition of the NF-κB and MAPK pathways. Front Pharmacol 2022; 13:919898. [PMID: 36003507 PMCID: PMC9394683 DOI: 10.3389/fphar.2022.919898] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Allyl methyl trisulfide (AMTS) is one major lipid-soluble organosulfur compound of garlic. Previous studies have reported the potential therapeutic effect of garlic on acute lung injury (ALI) or its severe condition acute respiratory distress syndrome (ARDS), but the specific substances that exert the regulatory effects are still unclear. In this study, we investigate the protective effects of AMTS on lipopolysaccharide (LPS)-induced ALI mice and explored the underlying mechanisms. In vivo experiments, ICR mice were pretreated with 25–100 mg/kg AMTS for 7 days and followed by intratracheal instillation of LPS (1.5 mg/kg). The results showed that AMTS significantly attenuated LPS-induced deterioration of lung pathology, demonstrated by ameliorative edema and protein leakage, and improved pulmonary histopathological morphology. Meanwhile, the expression of inflammatory mediators and the infiltration of inflammation-regulation cells induced by LPS were also inhibited. In vitro experiments also revealed that AMTS could alleviate inflammation response and inhibit the exaggeration of macrophage M1 polarization in LPS-induced RAW264.7 cells. Mechanistically, we identified that AMTS treatment could attenuate the LPS-induced elevation of protein expression of p-IκBα, nuclear NF-κB-p65, COX2, iNOS, p-P38, p-ERK1/2, and p-JNK. Collectively, these data suggest that AMTS could attenuate LPS-induced ALI and the molecular mechanisms should be related to the suppression of the NF-κB and MAPKs pathways.
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Affiliation(s)
- Shuo Wang
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, China
| | - Jinqian Liu
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, China
| | - Jing Dong
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, China
| | - Zongqiang Fan
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, China
| | - Fugui Wang
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, China
| | - Ping Wu
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, China
| | - Xiaojing Li
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, China
| | - Ruirui Kou
- School of Public Health, Shandong University, Jinan, Shandong, China
- *Correspondence: Ruirui Kou, ; Fang Chen,
| | - Fang Chen
- School of Pharmaceutical Sciences, Liaocheng University, Liaocheng, Shandong, China
- *Correspondence: Ruirui Kou, ; Fang Chen,
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16
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Jonigk D, Werlein C, Acker T, Aepfelbacher M, Amann KU, Baretton G, Barth P, Bohle RM, Büttner A, Büttner R, Dettmeyer R, Eichhorn P, Elezkurtaj S, Esposito I, Evert K, Evert M, Fend F, Gaßler N, Gattenlöhner S, Glatzel M, Göbel H, Gradhand E, Hansen T, Hartmann A, Heinemann A, Heppner FL, Hilsenbeck J, Horst D, Kamp JC, Mall G, Märkl B, Ondruschka B, Pablik J, Pfefferle S, Quaas A, Radbruch H, Röcken C, Rosenwald A, Roth W, Rudelius M, Schirmacher P, Slotta-Huspenina J, Smith K, Sommer L, Stock K, Ströbel P, Strobl S, Titze U, Weirich G, Weis J, Werner M, Wickenhauser C, Wiech T, Wild P, Welte T, von Stillfried S, Boor P. Organ manifestations of COVID-19: what have we learned so far (not only) from autopsies? Virchows Arch 2022; 481:139-159. [PMID: 35364700 PMCID: PMC8975445 DOI: 10.1007/s00428-022-03319-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/22/2022] [Accepted: 03/25/2022] [Indexed: 01/08/2023]
Abstract
The use of autopsies in medicine has been declining. The COVID-19 pandemic has documented and rejuvenated the importance of autopsies as a tool of modern medicine. In this review, we discuss the various autopsy techniques, the applicability of modern analytical methods to understand the pathophysiology of COVID-19, the major pathological organ findings, limitations or current studies, and open questions. This article summarizes published literature and the consented experience of the nationwide network of clinical, neuro-, and forensic pathologists from 27 German autopsy centers with more than 1200 COVID-19 autopsies. The autopsy tissues revealed that SARS-CoV-2 can be found in virtually all human organs and tissues, and the majority of cells. Autopsies have revealed the organ and tissue tropism of SARS-CoV-2, and the morphological features of COVID-19. This is characterized by diffuse alveolar damage, combined with angiocentric disease, which in turn is characterized by endothelial dysfunction, vascular inflammation, (micro-) thrombosis, vasoconstriction, and intussusceptive angiogenesis. These findings explained the increased pulmonary resistance in COVID-19 and supported the recommendations for antithrombotic treatment in COVID-19. In contrast, in extra-respiratory organs, pathological changes are often nonspecific and unclear to which extent these changes are due to direct infection vs. indirect/secondary mechanisms of organ injury, or a combination thereof. Ongoing research using autopsies aims at answering questions on disease mechanisms, e.g., focusing on variants of concern, and future challenges, such as post-COVID conditions. Autopsies are an invaluable tool in medicine and national and international interdisciplinary collaborative autopsy-based research initiatives are essential.
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Affiliation(s)
- Danny Jonigk
- Institute of Pathology, Hannover Medical School, Hannover, Germany.
| | | | - Till Acker
- Institute of Neuropathology, University Hospital Giessen and Marburg, Giessen, Germany
| | - Martin Aepfelbacher
- Institute of Medical Microbiology, Virology, and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kerstin U Amann
- Department of Nephropathology, University Hospital Erlangen-Nürnberg, Erlangen, Germany
| | - Gustavo Baretton
- Department of Pathology, University Hospital Dresden, Dresden, Germany
| | - Peter Barth
- Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Rainer M Bohle
- Department of Pathology, University Hospital Saarland Homburg, Homburg, Germany
| | - Andreas Büttner
- Institute of Forensic Medicine, University Medical Center Rostock, Rostock, Germany
| | - Reinhard Büttner
- Department of Pathology, University Hospital Cologne, Cologne, Germany
| | - Reinhard Dettmeyer
- Department of Legal Medicine, University Hospital Giessen and Marburg, Giessen, Germany
| | - Philip Eichhorn
- Department of Pathology, University Hospital Erlangen-Nürnberg, Erlangen, Germany
| | - Sefer Elezkurtaj
- Department of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Irene Esposito
- Department of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Katja Evert
- Department of Pathology, University Hospital Regensburg, Regensburg, Germany
| | - Matthias Evert
- Department of Pathology, University Hospital Regensburg, Regensburg, Germany
| | - Falko Fend
- Department of Pathology, University Hospital Tübingen, Tübingen, Germany
| | - Nikolaus Gaßler
- Department of Pathology, University Hospital Jena, Jena, Germany
| | - Stefan Gattenlöhner
- Department of Pathology, University Hospital Giessen and Marburg, Giessen, Germany
| | - Markus Glatzel
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Heike Göbel
- Department of Pathology, University Hospital Cologne, Cologne, Germany
| | - Elise Gradhand
- Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt, Germany
| | - Torsten Hansen
- Department of Pathology, University Hospital OWL of the Bielefeld University, Campus Lippe, Detmold, Germany
| | - Arndt Hartmann
- Department of Pathology, University Hospital Erlangen-Nürnberg, Erlangen, Germany
| | - Axel Heinemann
- Department of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank L Heppner
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany
- Cluster of Excellence, NeuroCure, Berlin, Germany
| | - Julia Hilsenbeck
- Department of Pathology, University Hospital Dresden, Dresden, Germany
| | - David Horst
- Department of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Jan C Kamp
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | - Gita Mall
- Department of Legal Medicine, University Hospital Jena, Jena, Germany
| | - Bruno Märkl
- General Pathology and Molecular Diagnostics, University Hospital Augsburg, Augsburg, Germany
| | - Benjamin Ondruschka
- Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jessica Pablik
- Department of Pathology, University Hospital Dresden, Dresden, Germany
| | - Susanne Pfefferle
- Institute of Medical Microbiology, Virology, and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexander Quaas
- Department of Pathology, University Hospital Cologne, Cologne, Germany
| | - Helena Radbruch
- Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christoph Röcken
- Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | | | - Wilfried Roth
- Department of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Martina Rudelius
- Institute of Pathology, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Peter Schirmacher
- Department of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Julia Slotta-Huspenina
- Department of Pathology, TUM School of Medicine of Technical University of Munich, Munich, Germany
| | - Kevin Smith
- Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt, Germany
| | - Linna Sommer
- Department of Pathology, University Hospital Dresden, Dresden, Germany
| | - Konrad Stock
- Department of Nephrology, TUM School of Medicine of Technical University of Munich, Munich, Germany
| | - Philipp Ströbel
- Department of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Stephanie Strobl
- Department of Pathology, University Medical Center Mainz, Mainz, Germany
| | - Ulf Titze
- Department of Pathology, University Hospital OWL of the Bielefeld University, Campus Lippe, Detmold, Germany
| | - Gregor Weirich
- Department of Pathology, TUM School of Medicine of Technical University of Munich, Munich, Germany
| | - Joachim Weis
- Department of Neuropathology, University Hospital RWTH Aachen, Aachen, Germany
| | - Martin Werner
- Institute for Surgical Pathology, Medical Center, University of Freiburg, Freiburg, Germany
| | - Claudia Wickenhauser
- Department of Pathology, University Hospital Halle (Saale), Halle (Saale), Germany
| | - Thorsten Wiech
- Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Peter Wild
- Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt, Germany
| | - Tobias Welte
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | | | - Peter Boor
- Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
- Department of Nephrology and Immunology, University Hospital RWTH Aachen, Aachen, Germany.
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17
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Eliseev MS, Zheliabina OV. Colchicine for the treatment of COVID-19: short path from theory to practice. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2022:71-79. [DOI: 10.21518/2079-701x-2022-16-11-71-79] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Colchicine is an alkaloid isolated from plants of the Colchicum genus. Colchicine has been used for thousands of years and remains one of the few drugs whose use remains relevant today. The therapeutic use of colchicine is widely known for gout, familial Mediterranean fever, Behcet’s disease, cardiovascular diseases (pericarditis, coronary heart disease, pericarditis, after coronary artery bypass grafting, etc.) and other diseases and is due to anti-inflammatory effects, which are based, including , inhibition of NLRP3 inflammasome and interleukin (IL)-1β production. The mechanisms of anti-inflammatory action of colchicine are diverse. It is primarily an inhibitor of mitosis and microtubule assembly. Colchicine destroys the structure of microtubules and reduces the elasticity and relaxation of neutrophils, thereby preventing the extravasation of neutrophils from blood vessels to the site of inflammation. Systemic inflammation is also a hallmark of coronavirus disease (COVID-19), which develops immunological disorders accompanied by the production of a large number of pro-inflammatory cytokines, including interleukin-1. Coronavirus disease 2019 (COVID-19), which has become the most urgent medical problem in the world in the last 2 years, given the mechanisms of inflammation similar to rheumatic diseases, is also considered a disease with the potential effectiveness of colchicine treatment. SARS-CoV-2 vaccines also have a trigger factor for the development of an exacerbation of arthritis. On average, colchicine use was associated with a 47% reduction in post-vaccination arthritis. This article provides an update on the mechanisms of action and current experience with colchicine in COVID-19, including in patients with microcrystalline arthritis.
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18
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Diao Y, Ding Q, Xu G, Li Y, Li Z, Zhu H, Zhu W, Wang P, Shi Y. Qingfei Litan Decoction Against Acute Lung Injury/Acute Respiratory Distress Syndrome: The Potential Roles of Anti-Inflammatory and Anti-Oxidative Effects. Front Pharmacol 2022; 13:857502. [PMID: 35677439 PMCID: PMC9168533 DOI: 10.3389/fphar.2022.857502] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 05/03/2022] [Indexed: 12/12/2022] Open
Abstract
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is an acute respiratory failure syndrome characterized by progressive arterial hypoxemia and dyspnea. Qingfei Litan (QFLT) decoction, as a classic prescription for the treatment of acute respiratory infections, is effective for the treatment of ALI/ARDS. In this study, the compounds, hub targets, and major pathways of QFLT in ALI/ARDS treatment were analyzed using Ultra high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) and systemic pharmacology strategies. UHPLC-MS identified 47 main components of QFLT. To explore its anti-inflammatory and anti-oxidative mechanisms, gene ontology (Go) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and network pharmacological analysis were conducted based on the main 47 components. KEGG enrichment analysis showed that TNF signaling pathway and Toll-like receptor signaling pathway may be the key pathways of ALI/ARDS. We explored the anti-inflammatory and anti-oxidative pharmacological effects of QFLT in treatment of ALI/ARDS in vivo and in vitro. QFLT suppressed the levels of proinflammatory cytokines and alleviated oxidative stress in LPS-challenged mice. In vitro, QFLT decreased the levels of TNF-α, IL-6, IL-1β secreted by LPS-activated macrophages, increased GSH level and decreased the LPS-activated reactive oxygen species (ROS) in lung epithelial A549 cells. This study suggested that QFLT may have anti-inflammatory and anti-oxidative effects on ALI/ARDS, combining in vivo and in vitro experiments with systemic pharmacology, providing a potential therapeutic strategy option.
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Affiliation(s)
- Yirui Diao
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Qi Ding
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.,Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, China
| | - Gonghao Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yadong Li
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zhenqiu Li
- Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hanping Zhu
- Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenxiang Zhu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.,Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, China
| | - Peng Wang
- Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yuanyuan Shi
- Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, China.,School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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19
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Regulation of proton partitioning in kinase-activating acute myeloid leukemia and its therapeutic implication. Leukemia 2022; 36:1990-2001. [PMID: 35624145 PMCID: PMC9343251 DOI: 10.1038/s41375-022-01606-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 11/21/2022]
Abstract
Gain-of-function kinase mutations are common in AML and usually portend an inferior prognosis. We reported a novel mechanism whereby kinase mutants induced intracellular alkalization characteristic in oncogenesis. Thirteen kinases were found to activate sodium/hydrogen exchanger (NHE1) in normal hematopoietic progenitors, of which FLT3-ITD, KRASG12D, and BTK phosphorylated NHE1 maintained alkaline intracellular pH (pHi) and supported survival of AML cells. Primary AML samples with kinase mutations also showed increased NHE1 phosphorylation and evidence of NHE1 addiction. Amiloride enhanced anti-leukemic effects and intracellular distribution of kinase inhibitors and chemotherapy. Co-inhibition of NHE1 and kinase synergistically acidified pHi in leukemia and inhibited its growth in vivo. Plasma from patients taking amiloride for diuresis reduced pHi of leukemia and enhanced cytotoxic effects of kinase inhibitors and chemotherapy in vitro. NHE1-mediated intracellular alkalization played a key pathogenetic role in transmitting the proliferative signal from mutated-kinase and could be exploited for therapeutic intervention in AML.
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20
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Chernov AS, Minakov AA, Kazakov VA, Rodionov MV, Rybalkin IN, Vlasik TN, Yashin DV, Saschenko LP, Kudriaeva AA, Belogurov AA, Smirnov IV, Loginova SY, Schukina VN, Savenko SV, Borisevich SV, Zykov KA, Gabibov AG, Telegin GB. A new mouse unilateral model of diffuse alveolar damage of the lung. Inflamm Res 2022; 71:627-639. [PMID: 35434745 PMCID: PMC9013507 DOI: 10.1007/s00011-022-01568-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 11/16/2022] Open
Abstract
Objective and design The existing biological models of diffuse alveolar damage (DAD) in mice have many shortcomings. To offset these shortcomings, we have proposed a simple, nonsurgical, and reproducible method of unilateral total damage of the left lung in ICR mice. This model is based on the intrabronchial administration of a mixture of bacterial lipopolysaccharide (LPS) from the cell wall of S. enterica and α-galactosylceramide (inducing substances) to the left lung. Methods Using computer tomography of the lungs with endobronchial administration of contrast material, we have been able to perform an operative intravital verification of the targeted delivery of the inducer. The model presented is characterized by more serious and homogeneous damage of the affected lung compared to the existing models of focal pneumonia; at the same time, our model is characterized by longer animal survival since the right lung remains intact. Results The model is also characterized by diffuse alveolar damage of the left lung, animal survival of 100%, abrupt increases in plasma levels of TNFa, INFg, and IL-6, and significant myocardial overload in the right heart. It can be used to assess the efficacy of innovative drugs for the treatment of DAD and ARDS as the clinical manifestations that are developed in patients infected with SARS-CoV-2. Morphological patterns of lungs in the noninfectious (“sterile”) model of DAD induced by LPS simultaneously with α-galactosylceramide (presented here) and in the infectious model of DAD induced by SARS-CoV-2 have been compared. Conclusion The DAD model we have proposed can be widely used for studying the efficacy of candidate molecules for the treatment of infectious respiratory diseases, such as viral pneumonias of different etiology, including SARS-CoV-2.
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21
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Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial. Intensive Care Med 2022; 48:36-44. [PMID: 34811567 PMCID: PMC8608557 DOI: 10.1007/s00134-021-06570-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/28/2021] [Indexed: 01/15/2023]
Abstract
PURPOSE Bone marrow-derived, allogeneic, multipotent adult progenitor cells demonstrated safety and efficacy in preclinical models of acute respiratory distress syndrome (ARDS). METHODS This phase 1/2 trial evaluated the safety and tolerability of intravenous multipotent adult progenitor cells in patients with moderate-to-severe ARDS in 12 UK and USA centres. Cohorts 1 and 2 were open-label, evaluating acute safety in three subjects receiving 300 or 900 million cells, respectively. Cohort 3 was a randomised, double-blind, placebo-controlled parallel trial infusing 900 million cells (n = 20) or placebo (n = 10) within 96 h of ARDS diagnosis. Primary outcomes were safety and tolerability. Secondary endpoints included clinical outcomes, quality of life (QoL) and plasma biomarkers. RESULTS No allergic or serious adverse reactions were associated with cell therapy in any cohort. At baseline, the cohort 3 cell group had less severe hypoxia. For cohort 3, 28-day mortality was 25% for cell vs. 45% for placebo recipients. Median 28-day free from intensive care unit (ICU) and ventilator-free days in the cell vs. placebo group were 12.5 (IQR 0,18.5) vs. 4.5 (IQR 0,16.8) and 18.5 (IQR 0,22) vs. 6.5 (IQR 0,18.3), respectively. A prospectively defined severe ARDS subpopulation (PaO2/FiO2 < 150 mmHg (20 kPa); n = 16) showed similar trends in mortality, ICU-free days and ventilator-free days favouring cell therapy. Cell recipients showed greater recovery of QoL through Day 365. CONCLUSIONS Multipotent adult progenitor cells were safe and well tolerated in ARDS. The clinical outcomes warrant larger trials to evaluate the therapeutic efficacy and optimal patient population.
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22
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Castillo RL, Gonzaléz-Candia A, Candia AA. Pathophysiology of Acute Respiratory Failure by CoV-2 Infection: Role of Oxidative Stress, Endothelial Dysfunction and Obesity. Open Respir Med J 2021. [DOI: 10.2174/1874306402115010076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) due to CoV-2 (coronavirus type 2) virus possess a particular risk of developing acute respiratory distress syndrome (ARDS) or SARS (severe acute respiratory syndrome coronavirus 2)-CoV2 in people with pre-existing conditions related to endothelial dysfunction and increased pro-inflammatory and pro-oxidant state. In between these conditions, chronic systemic inflammation related to obese patients is associated with the development of atherosclerosis, type 2 diabetes, and hypertension, comorbidities that adversely affect the clinical outcome in critical patients with COVID-19. Obesity affects up to 40% of the general population in the USA and more than 30% of the adult population in Chile. Until April 2021, 1,019,478 people have been infected, with 23,524 deaths. Given the coexistence of this worldwide obesity epidemic, COVID-19 negative outcomes are seriously enhanced in the current scenario. On the other hand, obesity is characterized by endothelial dysfunction observed in different vascular beds, an alteration which can be associated with impaired vasodilation, oxidative stress, and inflammatory events. Emerging evidence shows that obesity-related conditions such as endothelial dysfunction are associated with detrimental outcomes for COVID-19 evolution, especially if the patient derives to Intensive Care Units (ICU). This implies the need to understand the pathophysiology of the infection in the obese population, in order to propose therapeutic alternatives and public health policies, especially if the virus remains in the population. In this review, we summarize evidence about the pathogeny of Cov-2 infection in obese individuals and discuss how obesity-associated inflammatory and prooxidant status increase the severity of COVID-19.
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Esquivel-Ruiz S, González-Rodríguez P, Lorente JA, Pérez-Vizcaíno F, Herrero R, Moreno L. Extracellular Vesicles and Alveolar Epithelial-Capillary Barrier Disruption in Acute Respiratory Distress Syndrome: Pathophysiological Role and Therapeutic Potential. Front Physiol 2021; 12:752287. [PMID: 34887773 PMCID: PMC8650589 DOI: 10.3389/fphys.2021.752287] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) mediate intercellular communication by transferring genetic material, proteins and organelles between different cells types in both health and disease. Recent evidence suggests that these vesicles, more than simply diagnostic markers, are key mediators of the pathophysiology of acute respiratory distress syndrome (ARDS) and other lung diseases. In this review, we will discuss the contribution of EVs released by pulmonary structural cells (alveolar epithelial and endothelial cells) and immune cells in these diseases, with particular attention to their ability to modulate inflammation and alveolar-capillary barrier disruption, a hallmark of ARDS. EVs also offer a unique opportunity to develop new therapeutics for the treatment of ARDS. Evidences supporting the ability of stem cell-derived EVs to attenuate the lung injury and ongoing strategies to improve their therapeutic potential are also discussed.
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Affiliation(s)
- Sergio Esquivel-Ruiz
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Paloma González-Rodríguez
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain
| | - José A Lorente
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain.,Clinical Section, School of Medicine, European University of Madrid, Madrid, Spain
| | - Francisco Pérez-Vizcaíno
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Raquel Herrero
- Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain
| | - Laura Moreno
- Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain
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24
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Wang X, Yang B, Li Y, Luo J, Wang Y. AKR1C1 alleviates LPS‑induced ALI in mice by activating the JAK2/STAT3 signaling pathway. Mol Med Rep 2021; 24:833. [PMID: 34590152 PMCID: PMC8503743 DOI: 10.3892/mmr.2021.12473] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 08/05/2021] [Indexed: 01/08/2023] Open
Abstract
Acute lung injury (ALI) is a respiratory tract disease characterized by increased alveolar/capillary permeability, lung inflammation and structural damage to lung tissues, which can progress and transform into acute respiratory distress syndrome (ARDS). Although there are several treatment strategies available to manage this condition, there is still no specific cure for ALI. Aldo‑keto reductase family 1 member C1 (AKR1C1) is a member of the aldo‑keto reductase superfamily, and is a well‑known Nrf2 target gene and an oxidative stress gene. The aim of the present study was to investigate the effects of AKR1C1 on a lipopolysaccharide (LPS)‑induced ALI model. After mice received LPS treatment, the mRNA expression levels of AKR1C1 in the bronchoalveolar lavage fluid and serum were measured using reverse transcription‑quantitative PCR and its relationship with the inflammatory factors and malondialdehyde levels were determined using correlation analysis. Next, AKR1C1 was overexpressed or knocked out in mice, and subsequently ALI was induced in mice using LPS. The severity of ALI, oxidative stress and inflammation in the lungs were measured, and the potential involvement of the Janus kinase 2 (JAK2)/signal transduction activator of transcription 3 (STAT3) signaling pathway was assessed by measuring the changes of lung injury parameters after the agonists of JAK2/STAT3 pathway, including interleukin (IL)‑6 and colivelin, were administrated to mice. The results revealed that AKR1C1 expression was decreased in the LPS‑induced ALI mouse model. AKR1C1 expression was inversely correlated with serum tumor necrosis factor‑α, IL‑6 and malondialdehyde levels, and positively correlated with serum IL‑10 levels. AKR1C1 overexpression significantly attenuated lung injury, as shown by the changes in Evans blue leakage in the lung, lung wet/dry weight ratio, PaO2/FIO2 ratio, survival rate of mice and histological lung changes. In addition, the JAK2/STAT3 signaling pathway was significantly deactivated by AKR1C1+/+. When AKR1C1+/+ mice were treated with JAK2/STAT3 agonists, the effects of AKR1C1 overexpression on lung injury and oxidative stress were abolished. In conclusion, AKR1C1 may protect against oxidative stress and serve as a negative regulator of inflammation in ALI/ARDS. In addition, the JAK2/STAT3 signaling pathway could participate in the protective effects of AKR1C1 against ALI.
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Affiliation(s)
- Xianjun Wang
- Emergency Observation Ward, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222002, P.R. China
| | - Baocheng Yang
- Emergency Observation Ward, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222002, P.R. China
| | - Yuyu Li
- Emergency Observation Ward, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222002, P.R. China
| | - Jiye Luo
- Emergency Medicine Department, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222002, P.R. China
| | - Yanli Wang
- Emergency Medicine Department, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu 222002, P.R. China
- Emergency Medicine Department, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, Jiangsu 222002, P.R. China
- Emergency Medicine Department, Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, Jiangsu 222000, P.R. China
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Dorsal Push and Abdominal Binding Improve Respiratory Compliance and Driving Pressure in Proned Coronavirus Disease 2019 Acute Respiratory Distress Syndrome. Crit Care Explor 2021; 3:e0593. [PMID: 34841252 PMCID: PMC8613362 DOI: 10.1097/cce.0000000000000593] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
We describe seven proned patients with coronavirus disease 2019-related acute respiratory distress syndrome in whom a paradoxical decrease in driving pressure reversibly occurred during passive, volume-controlled ventilation when compressing the lower back by a sustained "dorsal push." We offer a potential explanation for these unexpected observations and suggest the possible importance of eliciting this response for lung-protective ventilation of similar patients. DESIGN/SETTING Case series at a single teaching hospital affiliated with the University of Minnesota. Measurements were recorded from continuously monitored airway pressure and flow data. PATIENTS Nonconsecutive and nonrandomized sample of coronavirus disease 2019 acute respiratory distress syndrome patients who were already prone and paralyzed for optimized lung protective clinical management while inhaling pure oxygen. INTERVENTIONS Sustained, firm manual pressure applied over the lower back in all patients, followed by abdominal binding in a subset of these. MEASUREMENTS AND MAIN RESULTS Respiratory system driving pressure declined and respiratory system compliance improved in seven patients with the dorsal push maneuver. In a subset of four of these, abdominal binding sustained those improvements over >3 hours. CONCLUSIONS Sustained compressive force applied to the dorsum of the passive and prone patient with severe respiratory failure due to coronavirus disease pneumonia may elicit a paradoxical response characterized by improved compliance and for a given tidal volume, lower plateau, and driving pressures. Such findings, which suggest end-tidal overinflation within the aerated part of the diseased lung despite the already compressed anterior chest wall of prone positioning, complement and extend those observations recently described for the supine position in coronavirus disease 2019 acute respiratory distress syndrome.
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26
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Zhang Z, Guo D, Ren Q. Successful Application of Extracorporeal Membrane Oxygenation in an Acute Tonsillitis Patient Complicated with Acute Respiratory Distress Syndrome: A Case Report. Open Access Emerg Med 2021; 13:499-502. [PMID: 34819758 PMCID: PMC8608020 DOI: 10.2147/oaem.s337568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 11/02/2021] [Indexed: 11/23/2022] Open
Abstract
Cases of acute tonsillitis, a common disease in the emergency department, are mostly mild and those complicated by severe pneumonia and acute respiratory distress syndrome are rarely reported.
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Affiliation(s)
- Zhufeng Zhang
- Emergency Department of Sandun District of Zhejiang Hospital, Hangzhou, Zhejiang, People's Republic of China
| | - Dongmei Guo
- Radiology Department of Sandun District of Zhejiang Hospital, Hangzhou, Zhejiang, People's Republic of China
| | - Qi Ren
- Qi Ren Intensive Care Unit of Sandun District of Zhejiang Hospital, Hangzhou, Zhejiang, People's Republic of China
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27
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Lu X, Ma W, Fan B, Li P, Gao J, Liu Q, Hu C, Li Y, Yao M, Ning H, Xing L. Integrating Network Pharmacology, Transcriptome and Artificial Intelligence for Investigating Into the Effect and Mechanism of Ning Fei Ping Xue Decoction Against the Acute Respiratory Distress Syndrome. Front Pharmacol 2021; 12:731377. [PMID: 34803679 PMCID: PMC8595141 DOI: 10.3389/fphar.2021.731377] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 09/20/2021] [Indexed: 01/19/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a high-mortality disease and lacks effective pharmacotherapy. A traditional Chinese medicine (TCM) formula, Ning Fei Ping Xue (NFPX) decoction, was demonstrated to play a critical role in alleviating inflammatory responses of the lung. However, its therapeutic effectiveness in ARDS and active compounds, targets, and molecular mechanisms remain to be elucidated. The present study investigates the effects of NFPX decoction on ARDS mice induced by lipopolysaccharides (LPS). The results revealed that NFPX alleviated lung edema evaluated by lung ultrasound, decreased lung wet/Dry ratio, the total cell numbers of bronchoalveolar lavage fluid (BALF), and IL-1β, IL-6, and TNF-α levels in BALF and serum, and ameliorated lung pathology in a dose-dependent manner. Subsequently, UPLC-HRMS was performed to establish the compounds of NFPX. A total of 150 compounds in NFPX were characterized. Moreover, integrating network pharmacology approach and transcriptional profiling of lung tissues were performed to predict the underlying mechanism. 37 active components and 77 targets were screened out, and a herbs-compounds-targets network was constructed. Differentially expressed genes (DEGs) were identified from LPS-treated mice compared with LPS combined with NFPX mice. GO, KEGG, and artificial intelligence analysis indicated that NFPX might act on various drug targets. At last, potential targets, HRAS, SMAD4, and AMPK, were validated by qRT-PCR in ARDS murine model. In conclusion, we prove the efficacy of NFPX decoction in the treatment of ARDS. Furthermore, integrating network pharmacology, transcriptome, and artificial intelligence analysis contributes to illustrating the molecular mechanism of NFPX decoction on ARDS.
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Affiliation(s)
- Xiaoxiao Lu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wentao Ma
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Baofeng Fan
- Air Force General Hospital PLA, Beijing, China
| | - Peng Li
- Department of Basic Sciences, Shanxi Agricultural University, Taigu, China
| | - Jing Gao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qiuhong Liu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunling Hu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengying Yao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hanbing Ning
- Department of Digestive Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lihua Xing
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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28
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Parker MFL, Blecha J, Rosenberg O, Ohliger M, Flavell RR, Wilson DM. Cyclic 68Ga-Labeled Peptides for Specific Detection of Human Angiotensin-Converting Enzyme 2. J Nucl Med 2021; 62:1631-1637. [PMID: 33637588 PMCID: PMC8612341 DOI: 10.2967/jnumed.120.261768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/11/2021] [Indexed: 01/30/2023] Open
Abstract
In this study, we developed angiotensin-converting enzyme 2 (ACE2)-specific, peptide-derived 68Ga-labeled radiotracers, motivated by the hypotheses that ACE2 is an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and that modulation of ACE2 in coronavirus disease 2019 (COVID-19) drives severe organ injury. Methods: A series of NOTA-conjugated peptides derived from the known ACE2 inhibitor DX600 were synthesized, with variable linker identity. Since DX600 bears 2 cystine residues, both linear and cyclic peptides were studied. An ACE2 inhibition assay was used to identify lead compounds, which were labeled with 68Ga to generate peptide radiotracers (68Ga-NOTA-PEP). The aminocaproate-derived radiotracer 68Ga-NOTA-PEP4 was subsequently studied in a humanized ACE2 (hACE2) transgenic model. Results: Cyclic DX-600-derived peptides had markedly lower half-maximal inhibitory concentrations than their linear counterparts. The 3 cyclic peptides with triglycine, aminocaproate, and polyethylene glycol linkers had calculated half-maximal inhibitory concentrations similar to or lower than the parent DX600 molecule. Peptides were readily labeled with 68Ga, and the biodistribution of 68Ga-NOTA-PEP4 was determined in an hACE2 transgenic murine cohort. Pharmacologic concentrations of coadministered NOTA-PEP (blocking) showed a significant reduction of 68Ga-NOTA-PEP4 signals in the heart, liver, lungs, and small intestine. Ex vivo hACE2 activity in these organs was confirmed as a correlate to in vivo results. Conclusion: NOTA-conjugated cyclic peptides derived from the known ACE2 inhibitor DX600 retain their activity when N-conjugated for 68Ga chelation. In vivo studies in a transgenic hACE2 murine model using the lead tracer, 68Ga-NOTA-PEP4, showed specific binding in the heart, liver, lungs and intestine-organs known to be affected in SARS-CoV-2 infection. These results suggest that 68Ga-NOTA-PEP4 could be used to detect organ-specific suppression of ACE2 in SARS-CoV-2-infected murine models and COVID-19 patients.
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Affiliation(s)
- Matthew F L Parker
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California
| | - Joseph Blecha
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California
| | - Oren Rosenberg
- Department of Medicine, University of California, San Francisco, San Francisco, California; and
| | - Michael Ohliger
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California
- Department of Radiology, Zuckerberg San Francisco General Hospital, San Francisco, California
| | - Robert R Flavell
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California
| | - David M Wilson
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California;
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Tocilizumab reduces COVID-19 mortality and pathology in a dose and timing-dependent fashion: a multi-centric study. Sci Rep 2021; 11:19728. [PMID: 34611251 PMCID: PMC8492686 DOI: 10.1038/s41598-021-99291-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 09/13/2021] [Indexed: 12/15/2022] Open
Abstract
Life-threatening COVID-19 is associated with strong inflammation, where an IL-6-driven cytokine storm appears to be a cornerstone for enhanced pathology. Nonetheless, the specific inhibition of such pathway has shown mixed outcomes. This could be due to variations in the dose of tocilizumab used, the stage in which the drug is administered or the severity of disease presentation. Thus, we performed a retrospective multicentric study in 140 patients with moderate to critical COVID-19, 79 of which received tocilizumab in variable standard doses (< 400 mg, 400–800 mg or > 800 mg), either at the viral (1–7 days post-symptom onset), early inflammatory (8–15) or late inflammatory (16 or more) stages, and compared it with standard treated patients. Mortality, reduced respiratory support requirements and pathology markers were measured. Tocilizumab significantly reduced the respiratory support requirements (OR 2.71, CI 1.37–4.85 at 95%) and inflammatory markers (OR 4.82, CI 1.4–15.8) of all patients, but mortality was only reduced (4.1% vs 25.7%, p = 0.03) when the drug was administered at the early inflammatory stage and in doses ranging 400–800 mg in severely-ill patients. Despite the apparent inability of Tocilizumab to prevent the progression of COVID-19 into a critical presentation, severely-ill patients may be benefited by its use in the early inflammatory stage and moderate doses.
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Li R, Hu S, Chen P, Jiang J, Cui G, Wang DW. Saving critically ill COVID-19 patients with mechanical circulatory support. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1221. [PMID: 34532358 PMCID: PMC8421987 DOI: 10.21037/atm-20-5169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 05/07/2021] [Indexed: 01/08/2023]
Abstract
Background Coronavirus disease 2019 (COVID-19) is an ongoing public health crisis that has led to many deaths due to multiple organ dysfunction syndromes (MODS). This article describes the clinical characteristics, management, and outcomes of critically ill COVID-19 patients who survived the disease through mechanical circulatory support (MCS). Methods We studied 25 critically ill COVID-19 patients who underwent MCS from January 20, 2020, to April 10, 2020, at the Tongji Hospital of Huazhong University of Science and Technology. Results Thirteen (52%) of the 25 patients survived with MCS support, while 12 (48%) died. At the time of their hospital admission, we identified significant differences in their peak cardiac troponin I (cTnI) and interleukin 6 (IL-6) levels, as well as in their lymphocyte count and C-reactive protein (CRP) levels. Cox proportional hazards regression model revealed that receipt of renal replacement therapy (RRT) was associated with an approximately 20-fold improvement in survival [hazard ratio (HR) =0.049, 95% confidence interval (CI) =0.008 to 0.305]. The number of days spent on extracorporeal membrane oxygenation (ECMO) support and the use of hydrogen (pH) at the time of MCS was also associated with an increase in survival. This contrasted with high-sensitivity C-reactive proteins (hs-CRP) and lactate, associated with a decrease in survival during MCS. Further analysis of the determinants relating to a COVID-19 patient’s chance of survival on/after MCS was also indicated by levels of IL-6 (β=0.009, P=0.006), IL-8 (β=0.031, P=0.020), and TNF-α (β=0.107, P=0.014), which saw a significant increase in the 12 patients who died. This contrasts with the non-significant decrease in IL-6, IL-8, and TNF-α levels in the 13 patients who survived. Conclusions These results indicate that pH, lactate, hs-CRP, ECMO duration, and RRT are important clinical determinants for assessing how MCS can increase the chances of critically ill COVID-19 patients surviving the disease.
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Affiliation(s)
- Rui Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Senlin Hu
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Peng Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Jiangang Jiang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Guanglin Cui
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
| | - Dao-Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
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Han J, Li G, Hou M, Ng J, Kwon MY, Xiong K, Liang X, Taglauer E, Shi Y, Mitsialis SA, Kourembanas S, El-Chemaly S, Lederer JA, Rosas IO, Perrella MA, Liu X. Intratracheal transplantation of trophoblast stem cells attenuates acute lung injury in mice. Stem Cell Res Ther 2021; 12:487. [PMID: 34461993 PMCID: PMC8404310 DOI: 10.1186/s13287-021-02550-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 08/08/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Acute lung injury (ALI) is a common lung disorder that affects millions of people every year. The infiltration of inflammatory cells into the lungs and death of the alveolar epithelial cells are key factors to trigger a pathological cascade. Trophoblast stem cells (TSCs) are immune privileged, and demonstrate the capability of self-renewal and multipotency with differentiation into three germ layers. We hypothesized that intratracheal transplantation of TSCs may alleviate ALI. METHODS ALI was induced by intratracheal delivery of bleomycin (BLM) in mice. After exposure to BLM, pre-labeled TSCs or fibroblasts (FBs) were intratracheally administered into the lungs. Analyses of the lungs were performed for inflammatory infiltrates, cell apoptosis, and engraftment of TSCs. Pro-inflammatory cytokines/chemokines of lung tissue and in bronchoalveolar lavage fluid (BALF) were also assessed. RESULTS The lungs displayed a reduction in cellularity, with decreased CD45+ cells, and less thickening of the alveolar walls in ALI mice that received TSCs compared with ALI mice receiving PBS or FBs. TSCs decreased infiltration of neutrophils and macrophages, and the expression of interleukin (IL) 6, monocyte chemoattractant protein-1 (MCP-1) and keratinocyte-derived chemokine (KC) in the injured lungs. The levels of inflammatory cytokines in BALF, particularly IL-6, were decreased in ALI mice receiving TSCs, compared to ALI mice that received PBS or FBs. TSCs also significantly reduced BLM-induced apoptosis of alveolar epithelial cells in vitro and in vivo. Transplanted TSCs integrated into the alveolar walls and expressed aquaporin 5 and prosurfactant protein C, markers for alveolar epithelial type I and II cells, respectively. CONCLUSION Intratracheal transplantation of TSCs into the lungs of mice after acute exposure to BLM reduced pulmonary inflammation and cell death. Furthermore, TSCs engrafted into the alveolar walls to form alveolar epithelial type I and II cells. These data support the use of TSCs for the treatment of ALI.
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Affiliation(s)
- Junwen Han
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Gu Li
- Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Minmin Hou
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
| | - Julie Ng
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
| | - Min-Young Kwon
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
| | - Kevin Xiong
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
| | - Xiaoliang Liang
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, 77024, USA
| | - Elizabeth Taglauer
- Department of Pediatrics, Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Yuanyuan Shi
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - S Alex Mitsialis
- Department of Pediatrics, Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Stella Kourembanas
- Department of Pediatrics, Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Souheil El-Chemaly
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
| | - James A Lederer
- Department of Surgery, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Ivan O Rosas
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
- Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, 77024, USA
| | - Mark A Perrella
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA
- Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Xiaoli Liu
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.
- Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
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32
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In-depth review of cardiopulmonary support in COVID-19 patients with heart failure. World J Cardiol 2021. [DOI: 10.4330/wjc.v13.i8.299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Raffaello WM, Huang I, Budi Siswanto B, Pranata R. In-depth review of cardiopulmonary support in COVID-19 patients with heart failure. World J Cardiol 2021; 13:298-308. [PMID: 34589166 PMCID: PMC8436686 DOI: 10.4330/wjc.v13.i8.298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/13/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 infection has spread worldwide and causing massive burden to our healthcare system. Recent studies show multiorgan involvement during infection, with direct insult to the heart. Worsening of the heart function serves as a predictor of an adverse outcome. This finding raises a particular concern in high risk population, such as those with history of preexisting heart failure with or without implantable device. Lower baseline and different clinical characteristic might raise some challenge in managing either exacerbation or new onset heart failure that might occur as a consequence of the infection. A close look of the inflammatory markers gives an invaluable clue in managing this condition. Rapid deterioration might occur anytime in this setting and the need of cardiopulmonary support seems inevitable. However, the use of cardiopulmonary support in this patient is not without risk. Severe inflammatory response triggered by the infection in combination with the preexisting condition of the worsening heart and implantable device might cause a hypercoagulability state that should not be overlooked. Moreover, careful selection and consideration have to be met before selecting cardiopulmonary support as a last resort due to limited resource and personnel. By knowing the nature of the disease, the interaction between the inflammatory response and different baseline profile in heart failure patient might help clinician to salvage and preserve the remaining function of the heart.
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Affiliation(s)
| | - Ian Huang
- Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung 40161, Indonesia
| | - Bambang Budi Siswanto
- Department of Cardiology and Vascular Medicine, National Cardiovascular Center Harapan Kita, Universitas Indonesia, Jakarta 11420, Indonesia
| | - Raymond Pranata
- Faculty of Medicine, Universitas Pelita Harapan, Tangerang 15810, Indonesia
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Chu CF, Sabath F, Fibi-Smetana S, Sun S, Öllinger R, Noeßner E, Chao YY, Rinke L, Winheim E, Rad R, Krug AB, Taher L, Zielinski CE. Convalescent COVID-19 Patients Without Comorbidities Display Similar Immunophenotypes Over Time Despite Divergent Disease Severities. Front Immunol 2021; 12:601080. [PMID: 34867933 PMCID: PMC8634761 DOI: 10.3389/fimmu.2021.601080] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 07/23/2021] [Indexed: 01/12/2023] Open
Abstract
COVID-19, the disease caused by SARS-CoV-2 infection, can assume a highly variable disease course, ranging from asymptomatic infection, which constitutes the majority of cases, to severe respiratory failure. This implies a diverse host immune response to SARS-CoV-2. However, the immunological underpinnings underlying these divergent disease courses remain elusive. We therefore set out to longitudinally characterize immune signatures of convalescent COVID-19 patients stratified according to their disease severity. Our unique convalescent COVID-19 cohort consists of 74 patients not confounded by comorbidities. This is the first study of which we are aware that excludes immune abrogations associated with non-SARS-CoV-2 related risk factors of disease severity. Patients were followed up and analyzed longitudinally (2, 4 and 6 weeks after infection) by high-dimensional flow cytometric profiling of peripheral blood mononuclear cells (PBMCs), in-depth serum analytics, and transcriptomics. Immune phenotypes were correlated to disease severity. Convalescence was overall associated with uniform immune signatures, but distinct immune signatures for mildly versus severely affected patients were detectable within a 2-week time window after infection.
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Affiliation(s)
- Chang-Feng Chu
- Institute of Virology, Technical University of Munich, Munich, Germany
- Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany
- Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Friedrich Schiller University, Jena, Germany
| | - Florian Sabath
- Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany
| | - Silvia Fibi-Smetana
- Institute of Biomedical Informatics, Graz University of Technology, Graz, Austria
| | - Shan Sun
- Institute of Virology, Technical University of Munich, Munich, Germany
- Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany
| | - Rupert Öllinger
- Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany
| | - Elfriede Noeßner
- Immunoanalytics-Tissue Control of Immunocytes, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
| | - Ying-Yin Chao
- Institute of Virology, Technical University of Munich, Munich, Germany
- Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany
| | - Linus Rinke
- Institute for Immunology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany
| | - Elena Winheim
- Institute for Immunology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany
| | - Roland Rad
- Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany
| | - Anne B. Krug
- Institute for Immunology, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-University Munich, Planegg-Martinsried, Germany
| | - Leila Taher
- Institute of Biomedical Informatics, Graz University of Technology, Graz, Austria
| | - Christina E. Zielinski
- Institute of Virology, Technical University of Munich, Munich, Germany
- Central Institute for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany
- Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Friedrich Schiller University, Jena, Germany
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35
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Kim B, Guaregua V, Chen X, Zhao C, Yeow W, Berg NK, Eltzschig HK, Yuan X. Characterization of a Murine Model System to Study MicroRNA-147 During Inflammatory Organ Injury. Inflammation 2021; 44:1426-1440. [PMID: 33566257 PMCID: PMC7873671 DOI: 10.1007/s10753-021-01427-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 12/15/2020] [Accepted: 01/26/2021] [Indexed: 12/13/2022]
Abstract
Inflammatory organ injury and sepsis have profound impacts on the morbidity and mortality of surgical and critical care patients. MicroRNAs are small RNAs composed of 20-25 nucleotides that have a significant contribution to gene regulation. MicroRNA-147 (miR-147), in particular, has been shown to have an emerging role in different physiological functions such as cell cycle regulation and inflammatory responses. However, animal model systems to study tissue-specific functions of miR-147 during inflammatory conditions in vivo are lacking. In the present study, we characterize miR-147 expression in different organs and cell types. Next, we generated a transgenic mouse line with a floxed miR-147 gene. Subsequently, we used this mouse line to generate mice with whole-body deletion of miR-147 (miR-147 -/-) by crossing "floxed" miR-147 mice with transgenic mice expressing Cre recombinase in all tissues (CMVcre mice). Systematic analysis of miR-147 -/- mice demonstrates normal growth, development, and off-spring. In addition, deletion of the target gene in different organs was successful at baseline or during inflammation, including the heart, intestine, stomach, liver, spleen, bone marrow, lungs, kidneys, or stomach. Moreover, miR-147 -/- mice have identical baseline inflammatory gene expression compared to C57BL/6 mice, except elevated IL-6 expression in the spleen (7.5 fold, p < 0.05). Taken together, our data show the successful development of a transgenic animal model for tissue and cell-specific deletion of miR-147 that can be used to study the functional roles of miR-147 during inflammatory organ injury.
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Affiliation(s)
- Boyun Kim
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX, 77030, USA
| | - Victor Guaregua
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX, 77030, USA
| | - Xuebo Chen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX, 77030, USA
| | - Chad Zhao
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Wanyi Yeow
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX, 77030, USA
| | - Nathaniel K Berg
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX, 77030, USA
| | - Holger K Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX, 77030, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX, 77030, USA.
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36
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Matthay MA, Thompson BT, Ware LB. The Berlin definition of acute respiratory distress syndrome: should patients receiving high-flow nasal oxygen be included? THE LANCET. RESPIRATORY MEDICINE 2021; 9:933-936. [PMID: 33915103 PMCID: PMC8075801 DOI: 10.1016/s2213-2600(21)00105-3] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/11/2021] [Accepted: 02/15/2021] [Indexed: 12/12/2022]
Abstract
The 2012 Berlin definition of acute respiratory distress syndrome (ARDS) provided validated support for three levels of initial arterial hypoxaemia that correlated with mortality in patients receiving ventilatory support. Since 2015, high-flow nasal oxygen (HFNO) has become widely used as an effective therapeutic support for acute respiratory failure, most recently in patients with severe COVID-19. We propose that the Berlin definition of ARDS be broadened to include patients treated with HFNO of at least 30 L/min who fulfil the other criteria for the Berlin definition of ARDS. An expanded definition would make the diagnosis of ARDS more widely applicable, allowing patients at an earlier stage of the syndrome to be recognised, independent of the need for endotracheal intubation or positive-pressure ventilation, with benefits for the testing of early interventions and the study of factors associated with the course of ARDS. We identify key questions that could be addressed in refining an expanded definition of ARDS, the implementation of which could lead to improvements in clinical practice and clinical outcomes for patients.
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Affiliation(s)
- Michael A Matthay
- Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
| | - B Taylor Thompson
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Lorraine B Ware
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
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37
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Berg NK, Li J, Kim B, Mills T, Pei G, Zhao Z, Li X, Zhang X, Ruan W, Eltzschig HK, Yuan X. Hypoxia-inducible factor-dependent induction of myeloid-derived netrin-1 attenuates natural killer cell infiltration during endotoxin-induced lung injury. FASEB J 2021; 35:e21334. [PMID: 33715200 PMCID: PMC8251729 DOI: 10.1096/fj.202002407r] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/21/2022]
Abstract
Sepsis and sepsis‐associated lung inflammation significantly contribute to the morbidity and mortality of critical illness. Here, we examined the hypothesis that neuronal guidance proteins could orchestrate inflammatory events during endotoxin‐induced lung injury. Through a targeted array, we identified netrin‐1 as the top upregulated neuronal guidance protein in macrophages treated with lipopolysaccharide (LPS). Furthermore, we found that netrin‐1 is highly enriched in infiltrating myeloid cells, particularly in macrophages during LPS‐induced lung injury. Transcriptional studies implicate hypoxia‐inducible factor HIF‐1α in the transcriptional induction of netrin‐1 during LPS treatment. Subsequently, the deletion of netrin‐1 in the myeloid compartment (Ntn1loxp/loxp LysM Cre) resulted in exaggerated mortality and lung inflammation. Surprisingly, further studies revealed enhanced natural killer cells (NK cells) infiltration in Ntn1loxp/loxp LysM Cre mice, and neutralization of NK cell chemoattractant chemokine (C‐C motif) ligand 2 (CCL2) reversed the exaggerated lung inflammation. Together, these studies provide functional insight into myeloid cell‐derived netrin‐1 in controlling lung inflammation through the modulation of CCL2‐dependent infiltration of NK cells.
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Affiliation(s)
- Nathaniel K Berg
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Jiwen Li
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.,Department of Cardiac Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Boyun Kim
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Tingting Mills
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Guangsheng Pei
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX, USA
| | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, TX, USA.,Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, TX, USA
| | - Xiangyun Li
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.,Department of Anesthesiology, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Xu Zhang
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA.,Center for Clinical and Translational Sciences, The University of Texas Health Science Center, Houston, TX, USA
| | - Wei Ruan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.,Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Holger K Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
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Ali FEM, Ahmed SF, Eltrawy AH, Yousef RS, Ali HS, Mahmoud AR, Abd-Elhamid TH. Pretreatment with Coenzyme Q10 Combined with Aescin Protects against Sepsis-Induced Acute Lung Injury. Cells Tissues Organs 2021; 210:195-217. [PMID: 34280918 DOI: 10.1159/000516192] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 03/26/2021] [Indexed: 11/19/2022] Open
Abstract
Sepsis-associated acute lung injury (ALI) is a critical condition characterized by severe inflammatory response and mitochondrial dysfunction. Coenzyme Q10 (CoQ10) and aescin (AES) are well-known for their anti-inflammatory activities. However, their effects on lipopolysaccharide (LPS)-induced lung injury have not been explored yet. Here, we asked whether combined pretreatment with CoQ10 and AES synergistically prevents LPS-induced lung injury. Fifty male rats were randomized into 5 groups: (1) control; (2) LPS-treated, rats received a single i.p. injection of LPS (8 mg/kg); (3) CoQ10-pretreated, (4) AES-pretreated, or (5) combined-pretreated; animals received CoQ10 (100 mg/kg), AES (5 mg/kg), or both orally for 7 days before LPS injection. Combined CoQ10 and AES pretreatment significantly reduced lung injury markers; 52.42% reduction in serum C-reactive protein (CRP), 53.69% in alkaline phosphatase (ALKP) and 60.26% in lactate dehydrogenase (LDH) activities versus 44.58, 37.38, and 48.6% in CoQ10 and 33.81, 34.43, and 39.29% in AES-pretreated groups, respectively. Meanwhile, combination therapy significantly reduced interleukin (IL)-1β and tumor necrosis factor (TNF)-α expressions compared to monotherapy (p < 0.05). Additionally, combination therapy prevented LPS-induced histological and mitochondrial abnormalities greater than separate drugs. Western blotting indicated that combination therapy significantly suppressed nucleotide-binding oligomerization domain (NOD)-like receptors-3 (NLRP-3) inflammasome compared to separate drugs (p < 0.05). Further, combination therapy significantly decreased the expression of signaling cascades, p38 mitogen-activated protein kinases (p38 MAPK), nuclear factor kappa B (NF-κB)-p65, and extracellular-regulated kinases 1/2 (ERK1/2) versus monotherapy (p < 0.05). Interestingly, combined pretreatment significantly downregulated high mobility group box-1 (HMGB1) by 72.93%, and toll-like receptor 4 (TLR4) by -0.93-fold versus 61.92%, -0.83-fold in CoQ10 and 38.67%, -0.70-fold in AES pretreatment, respectively. Our results showed for the first time that the enhanced anti-inflammatory effect of combined CoQ10 and AES pretreatment prevented LPS-induced ALI via suppression of NLRP-3 inflammasome through regulation of HMGB1/TLR4 signaling pathway and mitochondrial stabilization.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Salwa F Ahmed
- Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Amira H Eltrawy
- Department of Anatomy and Embryology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Reda S Yousef
- Department of Biochemistry, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Howaida S Ali
- Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt
- Department of Pharmacology, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Amany R Mahmoud
- Department of Human Anatomy and Embryology, Faculty of Medicine, Assiut University, Assiut, Egypt
- Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia
| | - Tarek H Abd-Elhamid
- Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt
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Triposkiadis F, Starling RC, Xanthopoulos A, Butler J, Boudoulas H. The Counter Regulatory Axis of the Lung Renin-Angiotensin System in Severe COVID-19: Pathophysiology and Clinical Implications. Heart Lung Circ 2021; 30:786-794. [PMID: 33454213 PMCID: PMC7831862 DOI: 10.1016/j.hlc.2020.11.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/17/2020] [Accepted: 11/22/2020] [Indexed: 12/15/2022]
Abstract
The severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which is responsible for coronavirus disease 2019 (COVID-19), uses angiotensin (ANG)-converting enzyme 2 (ACE2) as the entrance receptor. Although most COVID-19 cases are mild, some are severe or critical, predominantly due to acute lung injury. It has been widely accepted that a counter regulatory renin-angiotensin system (RAS) axis including the ACE2/ANG [1-7]/Mas protects the lungs from acute lung injury. However, recent evidence suggests that the generation of protective ANG [1-7] in the lungs is predominantly mediated by proinflammatory prolyl oligopeptidase (POP), which has been repeatedly demonstrated to be involved in lung pathology. This review contends that acute lung injury in severe COVID-19 is characterised by a) ACE2 downregulation and malfunction (inflammatory signalling) due to viral occupation, and b) dysregulation of the protective RAS axis, predominantly due to increased activity of proinflammatory POP. It follows that a reasonable treatment strategy in COVID-19-related acute lung injury would be delivering functional recombinant (r) ACE2 forms to trap the virus. Additionally, or alternatively to rACE2 delivery, the potential benefits resulting from lowering POP activity should also be explored. These treatment strategies deserve further investigation.
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Affiliation(s)
| | - Randall C Starling
- Kaufman Center for Heart Failure and Recovery, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Andrew Xanthopoulos
- Department of Cardiology, Larissa University General Hospital, Larissa, Greece
| | - Javed Butler
- Department of Medicine, University of Mississippi, Jackson, MS, USA
| | - Harisios Boudoulas
- Department of Medicine/Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA
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Merdji H, Mayeur S, Schenck M, Oulehri W, Clere-Jehl R, Cunat S, Herbrecht JE, Janssen-Langenstein R, Nicolae A, Helms J, Meziani F, Chenard MP. Histopathological features in fatal COVID-19 acute respiratory distress syndrome. Med Intensiva 2021; 45:261-270. [PMID: 34054173 PMCID: PMC7914021 DOI: 10.1016/j.medin.2021.02.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 02/05/2021] [Indexed: 12/15/2022]
Abstract
Background COVID-19 acute respiratory distress syndrome (ARDS) shares the common histological hallmarks with other forms of ARDS. However, the chronology of the histological lesions has not been well established. Objective To describe the chronological histopathological alterations in the lungs of patients with COVID-19 related ARDS. Design A prospective cohort study was carried out. Setting Intensive Care Unit of a tertiary hospital. Patients The first 22 consecutive COVID-19 deaths. Measurements Lung biopsies and histopathological analyses were performed in deceased patients with COVID-19 related ARDS. Clinical data and patient course were evaluated. Results The median patient age was 66 [63-74] years; 73% were males. The median duration of mechanical ventilation was 17 [8-24] days. COVID-19 induced pulmonary injury was characterized by an exudative phase in the first week of the disease, followed by a proliferative/organizing phase in the second and third weeks, and finally an end-stage fibrosis phase after the third week. Viral RNA and proteins were detected in pneumocytes and macrophages in a very early stage of the disease, and were no longer detected after the second week. Limitation Limited sample size. Conclusions The chronological evolution of COVID-19 lung histopathological lesions seems to be similar to that seen in other forms of ARDS. In particular, lung lesions consistent with potentially corticosteroid-sensitive lesions are seen.
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Key Words
- ACE2, angiotensin-converting enzyme 2
- AFOP, acute fibrinous and organizing pneumonia
- ARDS, acute respiratory distress syndrome
- COVID-19
- COVID-19 related acute respiratory distress syndrome
- COVID-19, coronavirus infectious disease
- DAD, diffuse alveolar damage
- HE, hematoxylin–eosin
- Histopathology
- ISH, in situ hybridization
- NMBD, neuromuscular blocking drugs
- RT-PCR, Reverse Transcriptase-Polymerase chain reaction
- SAPSII, simplified acute physiology score
- SARS-CoV-2
- SOFA, Sequential Organ Failure Assessment
- VILI, ventilator induced lung injury
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Affiliation(s)
- H Merdji
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
| | - S Mayeur
- Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - M Schenck
- Service de Médecine Intensive - Réanimation, Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - W Oulehri
- Service d'Anesthésie - Réanimation Chirurgicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Strasbourg, France
| | - R Clere-Jehl
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Strasbourg, France
| | - S Cunat
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - J-E Herbrecht
- Service de Médecine Intensive - Réanimation, Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - R Janssen-Langenstein
- Service de Médecine Intensive - Réanimation, Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - A Nicolae
- Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - J Helms
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Strasbourg, France
| | - F Meziani
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
| | - M-P Chenard
- Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- Centre de Ressources biologiques, Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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Merdji H, Mayeur S, Schenck M, Oulehri W, Clere-Jehl R, Cunat S, Herbrecht JE, Janssen-Langenstein R, Nicolae A, Helms J, Meziani F, Chenard MP. Histopathological features in fatal COVID-19 acute respiratory distress syndrome. Med Intensiva 2021; 45:261-270. [PMID: 34059216 PMCID: PMC8161799 DOI: 10.1016/j.medine.2021.02.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 02/05/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND COVID-19 acute respiratory distress syndrome (ARDS) shares the common histological hallmarks with other forms of ARDS. However, the chronology of the histological lesions has not been well established. OBJECTIVE To describe the chronological histopathological alterations in the lungs of patients with COVID-19 related ARDS. DESIGN A prospective cohort study was carried out. SETTING Intensive Care Unit of a tertiary hospital. PATIENTS The first 22 consecutive COVID-19 deaths. MEASUREMENTS Lung biopsies and histopathological analyses were performed in deceased patients with COVID-19 related ARDS. Clinical data and patient course were evaluated. RESULTS The median patient age was 66 [63-74] years; 73% were males. The median duration of mechanical ventilation was 17 [8-24] days. COVID-19 induced pulmonary injury was characterized by an exudative phase in the first week of the disease, followed by a proliferative/organizing phase in the second and third weeks, and finally an end-stage fibrosis phase after the third week. Viral RNA and proteins were detected in pneumocytes and macrophages in a very early stage of the disease, and were no longer detected after the second week. LIMITATION Limited sample size. CONCLUSIONS The chronological evolution of COVID-19 lung histopathological lesions seems to be similar to that seen in other forms of ARDS. In particular, lung lesions consistent with potentially corticosteroid-sensitive lesions are seen.
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Affiliation(s)
- H Merdji
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
| | - S Mayeur
- Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - M Schenck
- Service de Médecine Intensive - Réanimation, Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - W Oulehri
- Service d'Anesthésie - Réanimation Chirurgicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Strasbourg, France
| | - R Clere-Jehl
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Strasbourg, France
| | - S Cunat
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - J-E Herbrecht
- Service de Médecine Intensive - Réanimation, Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - R Janssen-Langenstein
- Service de Médecine Intensive - Réanimation, Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - A Nicolae
- Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - J Helms
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire (FHU) OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Strasbourg, France
| | - F Meziani
- Service de Médecine Intensive - Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France.
| | - M-P Chenard
- Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Centre de Ressources biologiques, Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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Lv H, Yuan X, Zhang J, Lu T, Yao J, Zheng J, Cai J, Xiao J, Chen H, Xie S, Ruan Y, An Y, Sui X, Yi H. Heat shock preconditioning mesenchymal stem cells attenuate acute lung injury via reducing NLRP3 inflammasome activation in macrophages. Stem Cell Res Ther 2021; 12:290. [PMID: 34001255 PMCID: PMC8127288 DOI: 10.1186/s13287-021-02328-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Acute lung injury (ALI) remains a common cause of morbidity and mortality worldwide, and to date, there is no effective treatment for ALI. Previous studies have revealed that topical administration of mesenchymal stem cells (MSCs) can attenuate the pathological changes in experimental acute lung injury. Heat shock (HS) pretreatment has been identified as a method to enhance the survival and function of cells. The present study aimed to assess whether HS-pretreated MSCs could enhance immunomodulation and recovery from ALI. MATERIALS AND METHODS HS pretreatment was performed at 42 °C for 1 h, and changes in biological characteristics and secretion functions were detected. In an in vivo mouse model of ALI, we intranasally administered pretreated umbilical cord-derived MSCs (UC-MSCs), confirmed their therapeutic effects, and detected the phenotypes of the macrophages in bronchoalveolar lavage fluid (BALF). To elucidate the underlying mechanisms, we cocultured pretreated UC-MSCs with macrophages in vitro, and the expression levels of inflammasome-related proteins in the macrophages were assessed. RESULTS The data showed that UC-MSCs did not exhibit significant changes in viability or biological characteristics after HS pretreatment. The administration of HS-pretreated UC-MSCs to the ALI model improved the pathological changes and lung damage-related indexes, reduced the proinflammatory cytokine levels, and modulated the M1/M2 macrophage balance. Mechanistically, both the in vivo and in vitro studies demonstrated that HS pretreatment enhanced the protein level of HSP70 in UC-MSCs, which negatively modulated NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in alveolar macrophages. These effects were partially reversed by knocking down HSP70 expression. CONCLUSION HS pretreatment can enhance the beneficial effects of UC-MSCs in inhibiting NLRP3 inflammasome activation in macrophages during ALI. The mechanism may be related to the upregulated expression of HSP70.
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Affiliation(s)
- Haijin Lv
- Department of Surgical Intensive Care Unit, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China.,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Xiaofeng Yuan
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of General Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jiebin Zhang
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Tongyu Lu
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jia Yao
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jun Zheng
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jianye Cai
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Jiaqi Xiao
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Haitian Chen
- Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.,Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Shujuan Xie
- Vaccine Research Institute of Sun Yat-sen University, Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ying Ruan
- Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
| | - Yuling An
- Department of Surgical Intensive Care Unit, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China. .,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
| | - Xin Sui
- Department of Surgical Intensive Care Unit, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China. .,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
| | - Huimin Yi
- Department of Surgical Intensive Care Unit, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, Guangdong Province, China. .,Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
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Zhang W, Wang Y, Li W, Wang G. The Association Between the Baseline and the Change in Neutrophil-to-Lymphocyte Ratio and Short-Term Mortality in Patients With Acute Respiratory Distress Syndrome. Front Med (Lausanne) 2021; 8:636869. [PMID: 34055826 PMCID: PMC8160236 DOI: 10.3389/fmed.2021.636869] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 04/22/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Two previous studies have shown that increased neutrophil to lymphocyte ratio (NLR) is associated with short-term prognosis in patients with acute respiratory distress syndrome (ARDS), but it is usually assessed as a single threshold value at baseline. We investigated the relationship between the baseline and the early change in NLR and 30-day mortality in patients with ARDS to evaluate the prognostic value of NLR baseline and NLR changes during the first 7 days after ICU admission. Methods: This is a retrospective cohort study, with all ARDS patients diagnosed according to the Berlin definition from the Medical Information Mart for Intensive Care III (MIMIC-III) database. We calculated the NLR by dividing the neutrophil count by the lymphocyte count. The multivariable logistic regression analysis was used to investigate the relationship between the baseline NLR and short-term mortality. Then the generalized additive mixed model was used to compare trends in NLR over time among survivors and non-survivors after adjusting for potential confounders. Results: A total of 1164 patients were enrolled in our study. Multivariable logistic regression analysis showed that after adjusting for confounders, elevated baseline NLR was a significant risk factor predicting 30-day mortality (OR 1.02, 95%CI 1.01, 1.03, P = 0.0046) and hospital mortality (OR 1.02, 95%CI 1.01, 1.03, P = 0.0003). The result of the generalized additive mixed model showed that the NLR decreased in the survival group and increased in the non-survival group gradually within 7 days after ICU admission. The difference between the two groups showed a trend of increase gradually and the difference increased by an average of 0.67 daily after adjusting for confounders. Conclusions: We confirmed that there was a positive correlation between baseline NLR and short-term mortality, and we found significant differences in NLR changes over time between the non-survival group and the survival group. The early increase in NLR was associated with short-term mortality in ARDS patients.
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Affiliation(s)
- Wei Zhang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Yadan Wang
- Ruibiao (Wuhan) Biotechnology Co. Ltd., Wuhan, China
| | - Weijie Li
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Guizuo Wang
- Department of Respiratory and Critical Care Medicine, Shaanxi Provincial People's Hospital, Xi'an, China
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Sayed M, Riaño D, Villar J. Novel criteria to classify ARDS severity using a machine learning approach. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2021; 25:150. [PMID: 33879214 PMCID: PMC8056190 DOI: 10.1186/s13054-021-03566-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 04/05/2021] [Indexed: 12/15/2022]
Abstract
Background Usually, arterial oxygenation in patients with the acute respiratory distress syndrome (ARDS) improves substantially by increasing the level of positive end-expiratory pressure (PEEP). Herein, we are proposing a novel variable [PaO2/(FiO2xPEEP) or P/FPE] for PEEP ≥ 5 to address Berlin’s definition gap for ARDS severity by using machine learning (ML) approaches. Methods We examined P/FPE values delimiting the boundaries of mild, moderate, and severe ARDS. We applied ML to predict ARDS severity after onset over time by comparing current Berlin PaO2/FiO2 criteria with P/FPE under three different scenarios. We extracted clinical data from the first 3 ICU days after ARDS onset (N = 2738, 1519, and 1341 patients, respectively) from MIMIC-III database according to Berlin criteria for severity. Then, we used the multicenter database eICU (2014–2015) and extracted data from the first 3 ICU days after ARDS onset (N = 5153, 2981, and 2326 patients, respectively). Disease progression in each database was tracked along those 3 ICU days to assess ARDS severity. Three robust ML classification techniques were implemented using Python 3.7 (LightGBM, RF, and XGBoost) for predicting ARDS severity over time. Results P/FPE ratio outperformed PaO2/FiO2 ratio in all ML models for predicting ARDS severity after onset over time (MIMIC-III: AUC 0.711–0.788 and CORR 0.376–0.566; eICU: AUC 0.734–0.873 and CORR 0.511–0.745). Conclusions The novel P/FPE ratio to assess ARDS severity after onset over time is markedly better than current PaO2/FiO2 criteria. The use of P/FPE could help to manage ARDS patients with a more precise therapeutic regimen for each ARDS category of severity. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-021-03566-w.
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Affiliation(s)
- Mohammed Sayed
- Banzai Research Group On Artificial Intelligence, Department of Computer Engineering, Universitat Rovira I Virgili, Av Paisos Catalans 26, 43007, Tarragona, Spain.
| | - David Riaño
- Banzai Research Group On Artificial Intelligence, Department of Computer Engineering, Universitat Rovira I Virgili, Av Paisos Catalans 26, 43007, Tarragona, Spain.
| | - Jesús Villar
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. .,Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr Negrín, Barranco de la Ballena s/n, 4th Floor -South Wing, 35019, Las Palmas de Gran Canaria, Spain. .,Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada.
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45
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Xu HR, Yang Q, Xiang SY, Zhang PH, Ye Y, Chen Y, Xu KW, Ren XY, Mei HX, Shen CX, Ma HY, Smith FG, Jin SW, Wang Q. Rosuvastatin Enhances Alveolar Fluid Clearance in Lipopolysaccharide-Induced Acute Lung Injury by Activating the Expression of Sodium Channel and Na,K-ATPase via the PI3K/AKT/Nedd4-2 Pathway. J Inflamm Res 2021; 14:1537-1549. [PMID: 33889010 PMCID: PMC8057837 DOI: 10.2147/jir.s299267] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/18/2021] [Indexed: 01/11/2023] Open
Abstract
Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are devastating clinical conditions characterized by pulmonary epithelial damage and protein-rich fluid accumulation in the alveolar spaces. Statins are a class of HMG-CoA reductase inhibitors, which exert cholesterol-lowering and anti-inflammatory effects. Methods Rosuvastatin (1 mg/kg) was injected intravenously in rats 12 h before lipopolysaccharide (LPS, 10 mg/kg) administration. Eight hours later after LPS challenge, alveolar fluid clearance (AFC) was detected in rats (n = 6–8). Rosuvastatin (0.3 µmol/mL) and LPS were cultured with primary rat alveolar type II epithelial cells for 8 h. Results Rosuvastatin obviously improved AFC and attenuated lung-tissue damage in ALI model. Moreover, it enhanced AFC by increasing sodium channel and Na,K-ATPase protein expression. It also up-regulated P-Akt via reducing Nedd4-2 in vivo and in vitro. Furthermore, LY294002 blocked the increase in AFC in response to rosuvastatin. Rosuvastatin-induced AFC was found to be partly rely on sodium channel and Na,K-ATPase expression via the PI3K/AKT/Nedd4-2 pathway. Conclusion In summary, the findings of our study revealed the potential role of rosuvastatin in the management of ALI/ARDS.
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Affiliation(s)
- Hao-Ran 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
| | - 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
| | - Shu-Yang 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
| | - Pu-Hong Zhang
- 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
| | - 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
| | - Yan Chen
- 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
| | - Ke-Wen Xu
- Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Xi-Ya Ren
- Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Hong-Xia 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
| | - Chen-Xi 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
| | - Hong-Yu Ma
- 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
| | - Fang-Gao Smith
- 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.,Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Sheng-Wei 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
| | - 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
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Easty DJ, Farr CJ, Hennessy BT. New Roles for Vitamin D Superagonists: From COVID to Cancer. Front Endocrinol (Lausanne) 2021; 12:644298. [PMID: 33868174 PMCID: PMC8045760 DOI: 10.3389/fendo.2021.644298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity.
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Affiliation(s)
- David J. Easty
- Department of Medical Oncology, Our Lady of Lourdes Hospital, Drogheda, Ireland
| | - Christine J. Farr
- Department of Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Bryan T. Hennessy
- Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Department of Oncology, Our Lady of Lourdes Hospital, Drogheda, Ireland
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Florian M, Wang JP, Deng Y, Souza-Moreira L, Stewart DJ, Mei SHJ. Gene engineered mesenchymal stem cells: greater transgene expression and efficacy with minicircle vs. plasmid DNA vectors in a mouse model of acute lung injury. Stem Cell Res Ther 2021; 12:184. [PMID: 33726829 PMCID: PMC7962085 DOI: 10.1186/s13287-021-02245-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 02/25/2021] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Acute lung injury (ALI) and in its severe form, acute respiratory distress syndrome (ARDS), results in increased pulmonary vascular inflammation and permeability and is a major cause of mortality in many critically ill patients. Although cell-based therapies have shown promise in experimental ALI, strategies are needed to enhance the potency of mesenchymal stem cells (MSCs) to develop more effective treatments. Genetic modification of MSCs has been demonstrated to significantly improve the therapeutic benefits of these cells; however, the optimal vector for gene transfer is not clear. Given the acute nature of ARDS, transient transfection is desirable to avoid off-target effects of long-term transgene expression, as well as the potential adverse consequences of genomic integration. METHODS Here, we explored whether a minicircle DNA (MC) vector containing human angiopoietin 1 (MC-ANGPT1) can provide a more effective platform for gene-enhanced MSC therapy of ALI/ARDS. RESULTS At 24 h after transfection, nuclear-targeted electroporation using an MC-ANGPT1 vector resulted in a 3.7-fold greater increase in human ANGPT1 protein in MSC conditioned media compared to the use of a plasmid ANGPT1 (pANGPT1) vector (2048 ± 567 pg/mL vs. 552.1 ± 33.5 pg/mL). In the lipopolysaccharide (LPS)-induced ALI model, administration of pANGPT1 transfected MSCs significantly reduced bronchoalveolar lavage (BAL) neutrophil counts by 57%, while MC-ANGPT1 transfected MSCs reduced it by 71% (p < 0.001) by Holm-Sidak's multiple comparison test. Moreover, compared to pANGPT1, the MC-ANGPT1 transfected MSCs significantly reduced pulmonary inflammation, as observed in decreased levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). pANGPT1-transfected MSCs significantly reduced BAL albumin levels by 71%, while MC-ANGPT1-transfected MSCs reduced it by 85%. CONCLUSIONS Overall, using a minicircle vector, we demonstrated an efficient and sustained expression of the ANGPT1 transgene in MSCs and enhanced the therapeutic effect on the ALI model compared to plasmid. These results support the potential benefits of MC-ANGPT1 gene enhancement of MSC therapy to treat ARDS.
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Affiliation(s)
- Maria Florian
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Jia-Pey Wang
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Yupu Deng
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | | | - Duncan J Stewart
- Ottawa Hospital Research Institute, Ottawa, ON, Canada
- The Ottawa Hospital, Ottawa, ON, Canada
- University of Ottawa, Ottawa, ON, Canada
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Abstract
IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
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Affiliation(s)
- Toshio Hirano
- National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Munn LL, Stylianopoulos T, Jain NK, Hardin CC, Khandekar MJ, Jain RK. Vascular Normalization to Improve Treatment of COVID-19: Lessons from Treatment of Cancer. Clin Cancer Res 2021; 27:2706-2711. [PMID: 33648989 DOI: 10.1158/1078-0432.ccr-20-4750] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/17/2021] [Accepted: 02/25/2021] [Indexed: 12/21/2022]
Abstract
The dramatic impact of the COVID-19 pandemic has resulted in an "all hands on deck" approach to find new therapies to improve outcomes in this disease. In addition to causing significant respiratory pathology, infection with SARS-CoV-2 (like infection with other respiratory viruses) directly or indirectly results in abnormal vasculature, which may contribute to hypoxemia. These vascular effects cause significant morbidity and may contribute to mortality from the disease. Given that abnormal vasculature and poor oxygenation are also hallmarks of solid tumors, lessons from the treatment of cancer may help identify drugs that can be repurposed to treat COVID-19. Although the mechanisms that result in vascular abnormalities in COVID-19 are not fully understood, it is possible that there is dysregulation of many of the same angiogenic and thrombotic pathways as seen in patients with cancer. Many anticancer therapeutics, including androgen deprivation therapy (ADT) and immune checkpoint blockers (ICB), result in vascular normalization in addition to their direct effects on tumor cells. Therefore, these therapies, which have been extensively explored in clinical trials of patients with cancer, may have beneficial effects on the vasculature of patients with COVID-19. Furthermore, these drugs may have additional effects on the disease course, as some ADTs may impact viral entry, and ICBs may accelerate T-cell-mediated viral clearance. These insights from the treatment of cancer may be leveraged to abrogate the vascular pathologies found in COVID-19 and other forms of hypoxemic respiratory failure.
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Affiliation(s)
- Lance L Munn
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Triantafyllos Stylianopoulos
- Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
| | - Natalie K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - C Corey Hardin
- Department of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Melin J Khandekar
- Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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50
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Zhang S, Chu C, Wu Z, Liu F, Xie J, Yang Y, Qiu H. IFIH1 Contributes to M1 Macrophage Polarization in ARDS. Front Immunol 2021; 11:580838. [PMID: 33519803 PMCID: PMC7841399 DOI: 10.3389/fimmu.2020.580838] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 12/02/2020] [Indexed: 12/22/2022] Open
Abstract
Accumulated evidence has demonstrated that the macrophage phenotypic switch from M0 to M1 is crucial in the initiation of the inflammatory process of acute respiratory distress syndrome (ARDS). Better insight into the molecular control of M1 macrophages in ARDS may identify potential therapeutic targets. In the current study, 36 candidate genes associated with the severity of ARDS and simultaneously involved in M1-polarized macrophages were first screened through a weighted network algorithm on all gene expression profiles from the 26 ARDS patients and empirical Bayes analysis on the gene expression profiles of macrophages. STAT1, IFIH1, GBP1, IFIT3, and IRF1 were subsequently identified as hub genes according to connectivity degree analysis and multiple external validations. Among these candidate genes, IFIH1 had the strongest connection with ARDS through the RobustRankAggreg algorithm. It was selected as a crucial gene for further investigation. For in vitro validation, the RAW264.7 cell line and BMDMs were transfected with shIFIH1 lentivirus and plasmid expression vectors of IFIH1. Cellular experimental studies further confirmed that IFIH1 was a novel regulator for promoting M1 macrophage polarization. Moreover, gene set enrichment analysis (GSEA) and in vitro validations indicated that IFIH1 regulated M1 polarization by activating IRF3. In addition, previous studies demonstrated that activation of IFIH1-IRF3 was stimulated by viral RNAs or RNA mimics. Surprisingly, the current study found that LPS could also induce IFIH1-IRF3 activation via a MyD88-dependent mechanism. We also found that only IFIH1 expression without LPS or RNA mimic stimulation could not affect IRF3 activation and M1 macrophage polarization. These findings were validated on two types of macrophages, RAW264.7 cells and BMDMs, which expanded the knowledge on the inflammatory roles of IFIH1 and IRF3, suggesting IFIH1 as a potential target for ARDS treatment.
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Affiliation(s)
- Shi Zhang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Cuilin Chu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zongsheng Wu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Feng Liu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Jianfeng Xie
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yi Yang
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Haibo Qiu
- Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
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