Publications by authors named "Marissa W Koh"

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

Am J Respir Crit Care Med 2021 Apr 13. Epub 2021 Apr 13.

Imperial College London, Anaesthetics & Intensive Care, London, United Kingdom of Great Britain and Northern Ireland;

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.
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http://dx.doi.org/10.1164/rccm.202009-3545OCDOI Listing
April 2021