A Novel Inflammatory Signal in Pulmonary Neutrophilia

描述(申请人提供)：胶原蛋白的分解释放一种三肽，PGP，它在体外对中性粒细胞(PMN)具有趋化作用。这里显示，呼吸道暴露于PGP会导致PMN的强劲、排他的内流，PMN是呼吸道病理中的关键细胞。慢性呼吸道暴露于这种多肽可重述呼吸道疾病的某些方面。此外，利用质谱仪，在急性暴露于雾化内毒素的动物的呼吸道中发现了PGP，并有助于PMN的趋化活性。PGP对PMN的趋化活性可能是由于与PMN特异的CXC趋化因子受体结合域(如IL-8)具有明显的结构相关性，该受体结合域含有该胶原蛋白序列或类似物。我们实验室开发的一种称为RTR的拮抗剂，在溶液中与Pgp结合，并阻断其体外和体内作用。可能是由于与PGP具有相同的结构，RTR还可以抑制IL-8的活性。因此，这项建议的总体目标是：1)表征Pgp对PMN的活性；2)确定Pgp的作用是否通过对趋化因子受体的作用而介导；以及3)确定Pgp或相关分子是否在体内产生，并在臭氧暴露等环境介导性呼吸道炎症的动物模型中向PMN发出信号。

DESCRIPTION (provided by applicant): Breakdown of collagen releases a tripeptide, PGP, that is chemotactic for neutrophils (PMN) in vitro. It is shown here that airway exposure to PGP causes a robust, exclusive influx of PMN, cells critical in respiratory pathology. Chronic airway exposure to this peptide recapitulates certain aspects of airway disease. Furthermore, using mass spectrometry, PGP is found in the airways of animals acutely exposed to aerosolized endotoxin and contributes to PMN chemotactic activity. The PMN chemotactic activity of PGP may be due to a marked structural relatedness to a receptor binding domain of CXC chemokines specific for PMN such as IL-8, which contain this collagen sequence or a close analog. An antagonist developed by our laboratory, termed RTR, binds PGP in solution and blocks its in vitro and in vivo effects. Likely as a result of shared structure with PGP, RTR also blocks IL-8 activity. Thus the overall goals of this proposal are to: 1) characterize the activity of PGP on PMN; 2) determine if PGP's effects are mediated through actions on chemokine receptors; and 3) determine whether PGP or a related molecule is generated in vivo and signals PMN in animal models of environmentally mediated airway inflammation like ozone exposure.