ROLE OF COMPLEMENT AND INFLAMMATORY CELLS IN LUNG INJURY

补体(C5)衍生的多肽被认为是 急性肺损伤(即成人呼吸窘迫综合征)，由 它们有能力导致中性粒细胞的隔离 肺血管系统中的白细胞(PMN)和随后的损害 内皮细胞。无论是C5衍生的责任分子的确切身份 中性粒细胞介导的损伤机制尚不清楚。 这项拟议的研究的目的是检验这一假设 血小板衍生因子和/或花生四烯酸代谢产物共同作用 用C5a和/或C5a Des Arg刺激的PMN改变 肺微血管内皮细胞。拟议的研究将 兔C5a和C5a-Des Arg AS的纯化及性质研究 以及旨在检验兔子之间相互作用的实验 C5衍生肽、兔中性粒细胞和兔内皮细胞。协同效应 多肽刺激的中性粒细胞、前列腺素和/或血小板因子之间的作用 血管通透性增加和PMN向肺泡迁移将是 在急性肺损伤动物模型中进行评估。自然的作用 正在发生的调节蛋白(即羧基肽酶N、共趋化因子和 趋化因子抑制剂)在调节这些相互作用中也将 在动物模型和体外实验中确定。这些研究的结果 应提供有关补语相互作用的新信息 系统、中性粒细胞、血小板和血管内皮细胞在发病中的作用 急性呼吸窘迫综合征。这些研究的结果也应该为 合理探讨急性呼吸窘迫综合征的防治措施

Complement (C5)-derived peptides have been implicated as being mediators of acute lung injury (i.e. adult respiratory distress syndrome, ARDS), by virtue of their ability to cause sequestration of polymorphonuclear leukocytes (PMN) in the pulmonary vasculature and subsequent damage to endothelium. Neither the precise identity of the responsible C5-derived peptide nor the mechanism of PMN-mediated injury has yet been determined. The objective of the proposed research is to test the hypothesis that platelet-derived factors and/or metabolites of arachidonic acid together with C5a- and/or C5a des Arg-stimulated PMN alter the integrity of pulmonary microvascular endothelial cells. The proposed studies will involve purification and characterization of rabbit C5a and C5a des Arg as well as experiments designed to examine interaction between rabbit C5-derived peptides, rabbit PMN and rabbit endothelial cells. Synergistic effects betwee peptide-stimulated PMN, prostanoids and/or platelet factors on increased vascular permeability and PMN emigration into alveoli will be assessed in animal models of acute lung injury. The role of naturally occurring regulatory proteins (i.e. carboxypeptidase N, cochemotaxin, and chemotactic factor inhibitor) in modulating these interactions will also be determined in animal models and in vitro. Results from these studies should provide new information concerning interaction of the complement system, neutrophils, platelets and vascular endothelium in the pathogenesis of ARDS. Results of these studies should also provide clues to the rational investigation of prophylactic and therapeutic measures for ARDS.