Activated protein C (APC) and other components of the protein C anticoagulant pathway can protect against death from severe sepsis by inhibiting both thrombosis and inflammation. The role of the endothelial cell protein C receptor (EPCR) and its potential interactions with protease activated receptors are incompletely understood, but preliminary data suggest a major role of EPCR in protection of the lung from bleomycin induced injury and hypoxia. We propose to study the impact of either over or under expression of EPCR on the development of acute lung injury induced by bacterial inhalation, hypoxia, hyperoxia and acid aspiration. The impact of altering EPCR expression on survival, cytokine elaboration, lung fibrosis, and thrombosis will be determined. The ability of APC to alter these pathological responses in animals over or under-expressing EPCR will be determined. EPCR expression appears to be induced on lung epithelial cells in response to bleomycin. We will determine the potential role of this induction by comparing the responses of EPCR null mice to mice selectively deficient in endothelial cell EPCR. Finally, it has been proposed that APC provides protection against acute inflammatory injury by activating PAR 1 in an EPCR dependent fashion. This possibility will be examined by determining the ability of APC to protect PAR 1 deficient mice from endotoxin inhalation with special attention to the lung pathology. We will attempt to generate mice deficient in both PAR 1 and EPCR to examine interactions between these receptors. These studies will provide insights into the mechanisms by which the protein C anticoagulant pathway protects the lung from injury.
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