A Novel Inflammatory Signal in Pulmonary Neutrophilia

肺中性粒细胞增多症中的一种新炎症信号

• 批准号: 6936298
• 负责人: NATHANIEL M WEATHINGTON
• 金额: $ 3.04万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936298
• 关键词: biological signal transduction; cell line; chemoattractants; chemokine; chemokine receptor; chemotaxis; clinical research; collagen; endotoxins; environmental exposure; flow cytometry; human subject; immune response; immunopathology; inflammation; interleukin 8; laboratory mouse; lipopolysaccharides; monoclonal antibody; neutrophil; nitrogen oxides; ozone; predoctoral investigator

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.

描述（由申请人提供）：胶原蛋白的分解释放了三肽PGP，它是嗜中性粒细胞（PMN）体外的趋化性。这里显示，气道暴露于PGP会导致PMN的稳健，独家涌入，在呼吸道病理中至关重要。慢性气道暴露于该肽可概括气道疾病的某些方面。此外，使用质谱法，在急性暴露于雾化内毒素的动物的气道中发现了PGP，并有助于PMN趋化活性。 PGP的PMN趋化活性可能是由于与PMN（例如IL-8）（例如IL-8）的CXC趋化因子的显着结构相关性，该结构趋化因子（例如IL-8），该结构包含该胶原蛋白序列或近距离类似物。由我们的实验室开发的拮抗剂称为RTR，在溶液中结合了PGP，并阻止其体外和体内效应。可能是与PGP共享结构的结果，RTR还阻止了IL-8活性。因此，该提案的总体目标是：1）表征PGP对PMN的活性； 2）确定PGP的作用是否是通过对趋化因子受体的作用介导的； 3）确定是否在体内产生PGP或相关分子，并在环境介导的气道炎症（如臭氧暴露）的动物模型中发出信号PMN。