The overall rationale for this project is to understand the molecular mechanisms that control polymorphonuclearneutrophil(PMN) migration into lumenal spaces at mucosal surfaces. There is abundant evidence, generated from many laboratories, that PMN migration across the epithelium in both lung and gastrointestinaltract is an important component of host defense against bacterial invasion at these surfaces. At the same time, PMN migration into these tissues can cause damage to the organs themselves, as PMN are important in initiating and perpetuating chronic inflammation that eventually leads to epithelial damage, scarring and fibrosis at epithelial surfaces. Chronic inflammation by PMN also has been associated with increased risk of cancer. While progress in understandingPMN migration to sites of inflammation has been rapid over the past decade, important gaps in understanding remain. In particular, little is understood about the molecular mechanisms involved in initial PMN attachment to the basolateral epithelial surface after their exit from the blood or about the transepithelial migration process itself. There are clues to understanding both these processes. Antibodies to the leukocyte integrin Mac-1 (CD11b/CD18, also known as alpha-M beta-2) prevent PMN adhesion to the epithelium, and antibodies to the ubiquitously expressed membrane protein CD47 inhibit transmigration without affecting initial adhesion. We propose to exploit these observations, our expertise in integrin and CD47 biology, and several unique reagents, including CD47-deficient and CD18-deficient mice, to reveal the molecular mechanisms of the two processes of PMN attachment to and transmigration through epithelial barriers. Specifically, we will address three critical questions: 1. Is PMN CD47 or epithelialCD47, or both, important in transepithelialmigration? 2. Does CD47 regulate interepithelialjunctions? 3. What isthe Mac-1 ligand on the basolateralsurface of epithelia? Completion of these studies will lead to increased understanding of a process critical to both host defense and disease pathogenesis and ultimatelywill enhance our abilityto controlthese processes.
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