Chemokine Compartmentalization and Neutrophil Accumulation in the Lung

描述（由申请人提供）：细胞通过激活吸引中性粒细胞的炎症机制对微生物做出反应，中性粒细胞部分依赖于ELR+ CXC趋化因子，其在特定区室（血浆、红细胞、空域、内皮等）中的定位影响其活性。我们假设趋化因子结合位点在非受体分子Duffy抗原趋化因子受体（DARC）和硫酸肝素蛋白聚糖（HSPG）上的可用性部分取决于趋化因子CXCL5和cxcl7的特定分子形式。我们进一步提出结合位点可用性调节肺中性粒细胞积聚。初步发现，小鼠CXCL5的靶向缺失对炎症的影响是两分的。CXCL5-/-小鼠对吸入LPS的反应是中性粒细胞积累减少，但对大肠杆菌的反应是中性粒细胞积累增加和细菌清除率提高。利用人类（培养的原代肺泡II型细胞）和小鼠系统（新生成的CXCL5和CXCL7的靶向缺失），我们追求3个特定目标，重点关注CXCL5在调节中性粒细胞积累和宿主防御中的潜在作用。在Aim 1中，我们定义了CXCL5和CXCL7对趋化因子清除和肺部炎症的影响。在Aim 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了趋化因子的跨肺泡运动，从而改变了炎症反应。在Aim 3中，我们将确定趋化因子结合在肺血管内腔室的位置和分子形式。了解趋化因子的配置及其相互作用将定义趋化因子的动力学和定位的基本机制，为诊断和预测算法提供希望，并允许因败血症和肺炎引起的疾病的治疗改变。

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.