Roles of EPCR and PAR I in Acute Lung Injury

活化蛋白C（APC）和蛋白C抗凝途径的其他组分可以通过抑制血栓形成和炎症来防止严重脓毒症引起的死亡。内皮细胞蛋白C受体（EPCR）的作用及其与蛋白酶激活受体的潜在相互作用尚不完全清楚，但初步数据表明，EPCR在保护肺免受博莱霉素诱导的损伤和缺氧中发挥重要作用。本研究旨在探讨EPCR过度表达或表达不足对细菌吸入、缺氧、高氧和酸吸入所致急性肺损伤发生发展的影响。将确定改变EPCR表达对存活率、细胞因子产生、肺纤维化和血栓形成的影响。将确定APC改变过表达或低表达EPCR的动物中的这些病理学应答的能力。EPCR表达似乎在肺上皮细胞上响应博来霉素而被诱导。我们将通过比较EPCR缺失小鼠与内皮细胞EPCR选择性缺陷小鼠的反应来确定这种诱导的潜在作用。最后，已经提出APC通过以EPCR依赖的方式激活PAR 1来提供针对急性炎性损伤的保护。这种可能性将通过测定APC保护PAR 1缺陷小鼠免受内毒素吸入的能力来检验，特别注意肺病理学。我们将尝试产生PAR 1和EPCR缺陷的小鼠，以检查这些受体之间的相互作用。这些研究将提供深入了解 蛋白C抗凝途径保护肺免受损伤的机制。

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.