Innate immunity forms a critical arm of host defense in the lungs, and neutrophils are an important component. This application focuses on understanding the molecular mechanisms that regulate the response of neutrophils. hanges in cytoskeletal structure and adhesivity are critical events in this response. The cytoskeletal changes induced by binding of mediators result in the initial sequestration of neutrophils within pulmonary capillaries. They take the form of increased cytoskeletal formation in a circumferential rim beneath the plasma membrane that leads to decreased ability to deform. Subsequent cytoskeletal rearrangements required for flattening and rawling along and between cells and through connective tissue are initiated by both ligation of adhesion molecules and binding of chemotaxic factors to their receptors. These rearrangements are dynamic and likely to ?esult from complex interactions between signaling pathways activated by adhesion and mediator receptors. Furthermore, the release of neutrophils from the bone marrow, necessary for mobilization of neutrophils needed for host defense in the lungs, likely involves similar cytoskeletal structural and adhesive changes initiated by circulating mediators. The working hypothesis for this proposal is that the response of neutrophils to nflammatory stimuli in the lung tissue and blood is modulated by a series of cytoskeletal structural and adhesive changes.
Aim 1 determines the signaling pathways leading to cytoskeletal rearrangements following nnding of mediators to receptors and the role of these rearrangements in neutrophil sequestration in vivo.
Aim 2 focuses on determining the interactions between adhesive and structural changes in neutrophils when they bind to pulmonary microvascular endothelial cells in vitro and in vivo through GDI l/CD18-dependent and - ndependent pathways. The goal of Aim 3 is to determine the role of adhesive and structural changes in the ?elease of neutrophils from the bone marrow.
Aim 4 determines the mechanisms through which CD44, a ?eceptor on neutrophils for hyaluronic acid, modulates neutrophil emigration in the lungs upon ligation. Our goal is to provide informationthat will ultimatelybe used to therapeutically modulate human disease.
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