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Secreted extracellular cyclophilin a is a novel mediator of ventilator induced lung injury.

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Title: Secreted extracellular cyclophilin a is a novel mediator of ventilator induced lung injury.
Authors: Koh, MW
Baldi, RF
Soni, S
Handslip, R
Tan, YY
O'Dea, KP
Malesevic, M
McAuley, DF
O'Kane, CM
Patel, BV
Takata, M
Wilson, MR
Item Type: Journal Article
Abstract: RATIONALE: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator induced lung injury. Extracellular Cyclophilin A is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to COVID-19 infection. OBJECTIVES: Here we explore the involvement of extracellular Cyclophilin A in the pathophysiology of ventilator-induced lung injury. METHODS: Mice were ventilated with low or high tidal volume for up to 3 hours, with or without blockade of extracellular Cyclophilin A signalling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretch to explore the cellular source of extracellular Cyclophilin A, and Cyclophilin A levels were measured in bronchoalveolar lavage fluid from acute respiratory distress syndrome patients, to evaluate clinical relevance. MEASUREMENTS AND MAIN RESULTS: High tidal volume ventilation in mice provoked a rapid increase in soluble Cyclophilin A levels in the alveolar space, but not plasma. In vivo ventilation and in vitro stretch experiments indicated alveolar epithelium as the likely major source. In vivo blockade of extracellular Cyclophilin A signalling substantially attenuated physiological dysfunction, macrophage activation and matrix metalloproteinases. Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated levels of extracellular Cyclophilin A within bronchoalveolar lavage. CONCLUSIONS: Cyclophilin A is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. Extracellular Cyclophilin A represents an exciting novel target for pharmacological intervention.
Issue Date: 15-Aug-2021
Date of Acceptance: 12-Apr-2021
URI: http://hdl.handle.net/10044/1/88395
DOI: 10.1164/rccm.202009-3545OC
ISSN: 1073-449X
Publisher: American Thoracic Society
Start Page: 421
End Page: 430
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Volume: 204
Issue: 4
Copyright Statement: © 2021 by the American Thoracic Society
Keywords: Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
mechanical ventilation
acute respiratory distress syndrome
matrix metalloproteinase
cyclosporin
animal model
SERUM CYCLOPHILIN
ACTIVATION
CONTRIBUTE
RELEASE
PATHWAY
MARKER
ICU
acute respiratory distress syndrome
animal model
cyclosporin
matrix metalloproteinase
mechanical ventilation
Animals
Anti-Inflammatory Agents
COVID-19
Cells, Cultured
Cyclophilin A
Humans
Inflammation
Male
Mice
Models, Animal
Respiration, Artificial
Respiratory Distress Syndrome
Respiratory Mucosa
SARS-CoV-2
Ventilator-Induced Lung Injury
Respiratory Mucosa
Cells, Cultured
Animals
Humans
Mice
Inflammation
Cyclophilin A
Anti-Inflammatory Agents
Respiration, Artificial
Models, Animal
Male
Ventilator-Induced Lung Injury
Respiratory Distress Syndrome
COVID-19
SARS-CoV-2
mechanical ventilation, acute respiratory distress syndrome, matrix metalloproteinase, cyclosporin, animal model
Respiratory System
11 Medical and Health Sciences
Publication Status: Published
Conference Place: United States
Embargo Date: 2022-04-12
Online Publication Date: 2021-04-13
Appears in Collections:Department of Surgery and Cancer
Faculty of Medicine