Chemokine Compartmentalization and Neutrophil Accumulation in the Lung

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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.