A Novel Inflammatory Signal in Pulmonary Neutrophilia

描述（由申请方提供）：胶原蛋白分解释放三肽PGP，其在体外对中性粒细胞（PMN）具有趋化性。这里显示，气道暴露于PGP导致PMN（在呼吸病理学中至关重要的细胞）的强有力的排他流入。慢性气道暴露于这种肽重现了气道疾病的某些方面。此外，使用质谱法，发现PGP存在于急性暴露于雾化内毒素的动物的气道中，并有助于PMN趋化活性。PGP的PMN趋化活性可能是由于与PMN特异性的CXC趋化因子（如IL-8）的受体结合结构域的显著结构相关性，所述CXC趋化因子含有这种胶原序列或类似物。我们实验室开发的一种拮抗剂，称为RTR，在溶液中结合PGP并阻断其体外和体内作用。可能由于与PGP共享结构，RTR也阻断IL-8活性。因此，本提案的总体目标是：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介导;以及3）确定PGP或相关分子是否在体内产生并在环境介导的气道炎症（如臭氧暴露）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.