PAR-1 exerts pro-apoptotic and pro-fibrotic effects following lung injury via the induction of TNF-alpha. (360G-Wellcome-084382_Z_07_Z)

Pulmonary fibrosis represents the end stage of a heterogeneous group of disorders in which excessive interstitial deposition of extracellular matrix proteins leads to airspace obliteration, respiratory insufficiency and premature death. There is strong evidence that procoagulant activity is increased in the lungs of these patients and that activation of the major thrombin signalling receptor, proteinase-activated receptor-1 (PAR1) induces the production/activation of pro-inflammatory and pro-fib rotic cytokines. PAR1 knockout mice (KO) are protected from bleomycin-induced pulmonary fibrosis and recent preliminary data generated by the host centre suggests that murine TNF-alpha expression is attenuated in these mice. There is further evidence that TNF-alpha is crucial for lymphocyte recruitment, TGF- expression, alveolar epithelial cell apoptosis and the development of bleomycin-induced fibrosis. Using PAR1 KO mice and cultured human lung cells, this project will examine the relationsh ip between PAR1 activation and TNF-alpha expression, with respect to the aforementioned parameters, in vivo and in vitro. Human disease relevance will be invoked by performing PAR1, TNF-alpha and apoptosis marker co-localisation studies using lung biopsy material. These studies will provide insights into the crosstalk between coagulation and cytokine networks in fibroproliferative lung disease, potentially identifying novel targets for therapeutic intervention.