Clinical Year 3 (post PhD)
"The Role of PAR-1 in Pulmonary Fibrosis"
Dr Rachel Chambers
Description of Project:
Apart from their role in haemostasis coagulation proteinases such as thrombin and Factor Xa (FXa) exert cellular effects via their major signalling receptor proteinase activated receptor-1(PAR1). We are interested in the role of the coagulation cascade and in particular FXa in driving the fibrotic response to both acute and chronic lung injury. Our studies have shown that the FXa precursor, coagulation zymogen FX is upregulated in experimentally- induced animal models of fibrosis as well as in patients with pulmonary fibrosis. In addition, FXa , via the release of a potent profibrotic cytokine TGF-?, is able to differentiate fibroblasts into highly, synthetic and contractile myofibroblasts which play a central role in the pathogenesis of pulmonary fibrosis. This data supports the notion of an extravascular coagulation system within the lung which is induced in response to lung injury and drives fibrosis by promoting myofibroblast differentiation. Selective FXa inhibitors are available and may therefore hold promise for interfering with the relentless progression of fibroproliferative lung diseases associated with excessive activation of the coagulation cascade.