Cellular / Molecular Biology of Inflammation and Repair

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DESCRIPTION (Verbatim from applicant's abstract) Wounds and their management remain the mainstay of surgical practice. Abnormal repair in diabetes, vascular disorders, malnutrition, infection and other clinical conditions challenge the practitioner and consume a substantial portion of health care dollars. The focal point of this project remains the study of the cellular and molecular biology of normal tissue repair, and is based on the premise that a full understanding of normal wound healing will provide essential footing to clinical intervention in abnormal repair. Specific Aims were designed by selecting among past fmdings those with the greatest potential to expand the mechanistic understanding of the regulation of inflammation and repair. Those observations and Specific Aims are: 1) Wound-derived macrophages actively induce apoptosis in wound polymorphonuclear leukocytes (PMN) through a specific effector mechanism comprising, at least, the expression of b3 integrins and membrane-bound TNF-a on the macrophage surface. Experiments proposed in Specific Aim I will expand on these paradigm-shifting observations by examining the role of TNF-a and its receptors in repair and by further defining the mechanisms of macrophage-dependent PMN apoptosis. 2) Inducible nitric oxide synthase (iNOS) is expressed in wounds mostly in macrophages and during the first 72 h of repair. Lack of iNOS is associated with impaired wound healing. Specific Aim II will focus on the mechanistic role of iNOS-derived NO in the process of tissue repair. 3) Cells producing NO exhibit metabolic injury with suppressed substrate oxidation and increased glycolysis. Work during this period demonstrated that NO induces a novel acyl phosphatase activity in the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase that uncouples carbon flux in glycolysis from ATP production. Specific Aim III will continue work in this area by investigating specifics of glycolytic energy production in inflammatory cells. Completion of the proposed studies should further the understanding of the cellular and molecular events that underlie the processes resulting in normal tissue repair.