Procoagulant signalling in acute lung injury.

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Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS) are devastating and often fatal clinical syndromes caused as a result of infection, trauma, exposure to lung toxicants and adverse drug reactions. The lungs respond to injury by becoming inflamed, accumulating fluid and activating a system of blood clotting proteins (coagulation factors) in order to temporarily plug damaged blood vessels. Aside from their roles in clotting, many of these coagulation factors can also directly influence inflammation. Under certain conditions their action can trigger an exaggerated inflammatory response, resulting in escalation of lung damage and in many cases, death of affected individuals. There are currently few effective therapies for ALI/ARDS, so that new treatments are urgently required. Our work with a new compound, has shown that a cell surface receptor, proteinase activated receptor-1 (PAR1), mediates the cellular effects of coagulation proteinases in an animal model of this condition and might offer promise as a novel therapeutic target. This project will begin to identify the potential of PAR1 antagonists in pre-clinical studies and will elucidate the mechanisms by which this receptor mediates lung inflammation and lung fluid accumulation, using an integrated experimental approach involving an experimental model of lung injury, cultured cells and patient biopsy and lung lavage samples. This information will help in the development of specific and effective therapies for these devastating conditions.