Koh, Marissa W;
Baldi, Rhianna F;
Soni, Sanooj;
Handslip, Rhodri;
Tan, Ying Ying;
O'Dea, Kieran P;
Malesevic, Miroslav;
... Wilson, Michael R; + view all
(2021)
Secreted Extracellular Cyclophilin A is a Novel Mediator of Ventilator Induced Lung Injury.
American Journal of Respiratory and Critical Care Medicine
, 204
(4)
pp. 421-430.
10.1164/rccm.202009-3545OC.
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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.
| Type: | Article |
|---|---|
| Title: | Secreted Extracellular Cyclophilin A is a Novel Mediator of Ventilator Induced Lung Injury |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1164/rccm.202009-3545OC |
| Publisher version: | https://doi.org/10.1164/rccm.202009-3545OC |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | mechanical ventilation, acute respiratory distress syndrome, matrix metalloproteinase, cyclosporin, animal model |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10154720 |
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