Secreted extracellular cyclophilin a is a novel mediator of ventilator induced lung injury.
File(s)
Accepted version
Author(s)
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.
Date Issued
2021-08-15
Date Acceptance
2021-04-12
Citation
American Journal of Respiratory and Critical Care Medicine, 2021, 204 (4), pp.421-430
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
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33848447
Subjects
mechanical ventilation, acute respiratory distress syndrome, matrix metalloproteinase, cyclosporin, animal model
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2021-04-13