Secreted Extracellular Cyclophilin A is a Novel Mediator of Ventilator Induced Lung Injury

Marissa W. Koh, Rhianna F. Baldi, Sanooj Soni, Rhodri Handslip, Ying Ying Tan, Kieran P. O'Dea, Miroslav Malesevic, Daniel F. McAuley, Cecilia M. O'Kane, Brijesh V Patel, Masao Takata, Michael R. Wilson

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournalAmerican Journal of Respiratory and Critical Care Medicine
Early online date13 Apr 2021
DOIs
Publication statusEarly online date - 13 Apr 2021

Keywords

  • Critical Care and Intensive Care Medicine
  • Pulmonary and Respiratory Medicine

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