Chemokine Compartmentalization and Neutrophil Accumulation in the Lung

描述（由申请方提供）：细胞通过激活炎症机制对微生物进行反应，炎症机制吸引中性粒细胞，部分依赖于ELR+ CXC趋化因子，其在特定隔室（血浆、红细胞、气腔、内皮等）中的定位影响其活性。我们假设，趋化因子结合位点的非受体分子达菲抗原受体趋化因子（DARC）和硫酸乙酰肝素蛋白聚糖（HSPG）的CXCL 1的可用性，部分是由特定的分子形式的趋化因子CXCL 5和7。我们进一步提出，结合位点的可用性调节中性粒细胞在肺中的积累。初步研究结果表明，CXCL 5在小鼠中的靶向缺失对炎症产生二分作用。CXCL 5-/-小鼠对吸入LPS的反应是中性粒细胞积聚减少，但对大肠杆菌的反应是中性粒细胞积聚增加和细菌清除改善。使用人（培养的原代肺泡II型细胞）和鼠系统（新产生的CXCL 5和CXCL 7的靶向缺失），我们追求3个特定目标，集中于CXCL 5在调节中性粒细胞积累和宿主防御中的潜在作用。目的1：明确CXCL 5和CXCL 7对趋化因子清除和肺部炎症的作用。在目的2中，我们提出确定CXCL 5和CXCL 7与DARC和HSPG结合在多大程度上改变趋化因子的跨肺泡运动，从而改变炎症反应。在目标3中，我们将确定在肺血管腔内室结合的趋化因子的位点和分子形式。了解趋化因子的处置，以及它们如何相互作用将定义趋化因子的动力学和定位的基本机制，提供诊断和预测算法的希望，并允许由于败血症和肺炎引起的疾病的治疗改变。 公共卫生相关性：小鼠中CXCL 5的靶向缺失增加了嗜中性粒细胞对大肠杆菌肺炎的反应并改善了细菌清除CXCL 5，并且密切相关的趋化因子CXCL 7独特地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结合分子隔离和呈递的机制，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.