Acute respiratory distress syndrome (ARDS) remains a significant cause of mortality and morbidity within the Intensive Care Unit. Despite increasing understanding of its pathogenesis in the past 50 years, management remains purely supportive with mechanical ventilation (MV) forming the mainstay of treatment. However, MV itself can worsen pre-existing ARDS, a phenomenon known as ventilator-induced lung injury (VILI). Since exposure to MV remains largely unavoidable, it is important that clinicians are able to limit the damage that occurs when patients are ventilated. While pharmacotherapies aimed at mitigating the inflammatory component of VILI have always been an attractive approach, to date, none have been shown to be successful in clinical trials. This suggests that there are still gaps in our current understanding of the disease and highlights the importance of studies investigating mechanistic pathways of ARDS.

In this thesis, we explore the role of the cyclophilin A (CypA):CD147 signalling axis in VILI. CypA is a ubiquitously distributed protein. Although previous research has focussed on its intracellular roles, recent studies suggest the involvement of extracellular CypA and its primary receptor CD147 in inflammatory diseases. We hypothesise that CypA is secreted into the alveolar space following epithelial insult where it can then interact with CD147 to promote inflammation and injury.

We have shown, for the first time, the involvement of CypA in VILI in animal models as well as in human ARDS patients. CypA is produced locally within the lungs at an early time point, most likely by alveolar epithelial cells. In vitro, recombinant CypA induces activation of macrophages, suggesting it is more than a mere biomarker of injury. Lastly, inhibition of extracellular CypA in vivo leads to improved survival and impressive attenuation physiological dysfunction, providing further evidence that CypA does play a role in the pathogenesis of VILI.