Chemokine Compartmentalization and Neutrophil Accumulation in the Lung

描述(由申请人提供)：细胞对微生物的反应是通过激活炎症机制来吸引中性粒细胞，部分依赖于ELR+CXC趋化因子，其在特定隔室(血浆、红细胞、空泡、内皮等)中的定位影响其活性。初步研究结果表明，CXCL5在小鼠体内的靶向缺失对炎症具有双重作用。CXCL5-/-小鼠对吸入内毒素的反应是中性粒细胞聚集减少，但对大肠杆菌的反应是中性粒细胞聚集增加和细菌清除改善。使用人(培养中的原代肺泡II型细胞)和小鼠系统(新产生的CXCL5和CXCL7的靶向缺失)，我们追求三个特定的目标，重点是CXCL5在调节中性粒细胞聚集和宿主防御方面的潜在作用。在目标1中，我们定义了CXCL5和CXCL7在趋化因子清除和肺部炎症中的作用。在目标2中，我们建议确定CXCL5和CXCL7与DARC和HSPG结合在多大程度上改变趋化因子的跨肺运动，从而改变炎症反应。在目标3中，我们将确定结合在肺血管内室的趋化因子的位置和分子形式。了解趋化因子的分布以及它们如何相互作用将定义趋化因子动力学和定位的基本机制，为诊断和预测算法提供希望，并允许脓毒症和肺炎引起的疾病的治疗性改变。 公共卫生相关性：在小鼠中定向删除CXCL5可以增加中性粒细胞对大肠杆菌肺炎的反应，并改善细菌清除CXCL5，而密切相关的趋化因子CXCL7唯一适合于影响许多其他趋化因子与其非受体结合分子DARC和HSPG的结合。通过强调趋化因子被隔离并通过结合分子呈现的机制，这些研究提出了一种新的肺部炎症反应模型。

DESCRIPTION (provided by applicant): Cells react to microorganisms by activating inflammatory mechanisms that attract neutrophils, dependent in part on ELR+ CXC chemokines, whose localization within specific compartments (plasma, erythrocyte, airspace, endothelium among others) influences their activity. We hypothesize that the availability of chemokine binding sites on the non-receptor molecules Duffy antigen receptor for chemokines (DARC) and heparan sulfate proteoglycans (HSPG) for CXCL1 is determined, in part, by specific molecular forms of the chemokines CXCL5 and 7. We further propose that binding site availability regulates neutrophil accumulation in the lung. Preliminary findings indicate that targeted deletion of CXCL5 in mouse exerts dichotomous effects on inflammation. CXCL5-/- mice respond to inhaled LPS with decreased neutrophil accumulation, but respond to E coli with increased neutrophil accumulation and improved bacterial clearance. Using both human (primary alveolar type II cells in culture) and murine systems (newly- generated targeted deletions of CXCL5 and CXCL7), we pursue 3 specific aims focused on the potential role of CXCL5 in modulating neutrophil accumulation and host defense. In Aim 1, We define the effect of CXCL5 and CXCL7 on chemokine scavenging and lung inflammation. In Aim 2, we propose to determine the extent to which CXCL5 and CXCL7 binding to DARC and HSPG modifies transalveolar movement of chemokines and hence, inflammatory responses. In Aim 3 we will determine the sites and molecular forms of chemokines bound in the lung endovascular compartment. Understanding the disposition of chemokines, and how they interact will define fundamental mechanisms of kinetics and localization of chemokines, offer promise in diagnostic and predictive algorithms, and permit therapeutic alteration of disease due to sepsis and pneumonia. PUBLIC HEALTH RELEVANCE: Targeted deletion of CXCL5 in mouse increases the neutrophil response to E coli pneumonia and improves bacterial clearance CXCL5, and the closely related chemokine CXCL7 are uniquely suited to influence the binding of many other chemokines to their non-receptor binding molecules DARC and HSPG. By highlighting mechanisms by which chemokines are sequestered and presented by binding molecules these studies present a novel model of the inflammatory response in the lung.