Lung inflammation contributes to morbidity and mortality in many critically ill patients. The major goals of this proposal are to understand the mechanisms that regulate cell traffic during inflammatory processes in the lungs and to develop strategies that could be used to limit some types of lung inflammation. Chemotactic factors generated by alveolar macrophage and other cells in the lung airspaces recruit leukocytes from the bloodstream into the lungs. These leukocytes amplify inflammatory reactions and their products may contribute to lung injury in some circumstances. Because the alveolar macrophage is a primary cell that recognizes bacteria and foreign particulate in the airspaces, we hypothesize that alveolar macrophage products are important in initiating and sustaining inflammatory responses in the lungs.
The Specific Aims of this proposal are: 1) to identify the major peptide chemoattractants for neutrophils (PMN) and monocytes (MN) that are produced by alveolar macrophage; 2) to develop specific approaches to inhibit the function of these peptides; 3) to define the regulation of these products in response to bacterial products; and 4) to compare the potency of these endogenous chemoattractants with the potency of chemoattractants produced by Gram negative and Gram positive bacteria. In the studies proposed, we will determine the relative contribution of peptide chemoattractants to the chemotactic activity for PMN and MN produced by stimulated alveolar macrophage; we will clone the receptors for IL-8 and MCP-1, two major PMN and MN chemoattractants, respectively; we will raise monoclonal antibodies to these receptors that inhibit receptor-ligand interactions and test these antibodies for their ability to block leukocyte migration in vitro and in vivo; and we will compare the relative potency of the alveolar macrophage derived peptides with the products of Gram positive and Gram negative bacteria in order to determine whether inhibition of endogenous chemotactic signals poses a potential risk to the host during bacterial infections. These studies will identify strategies to limit inflammation in the lungs that could lead to improved therapy in critically ill patients with diffuse lung injury.
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