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.
| Crane, Meredith J; Daley, Jean M; van Houtte, Olivier et al. (2014) The monocyte to macrophage transition in the murine sterile wound. PLoS One 9:e86660 |
| Brancato, Samielle K; Thomay, Alan A; Daley, Jean M et al. (2013) Toll-like receptor 4 signaling regulates the acute local inflammatory response to injury and the fibrosis/neovascularization of sterile wounds. Wound Repair Regen 21:624-633 |
| Brancato, Samielle K; Albina, Jorge E (2011) Wound macrophages as key regulators of repair: origin, phenotype, and function. Am J Pathol 178:19-25 |
| Daley, Jean M; Brancato, Samielle K; Thomay, Alan A et al. (2010) The phenotype of murine wound macrophages. J Leukoc Biol 87:59-67 |
| Thomay, Alan A; Daley, Jean M; Sabo, Edmond et al. (2009) Disruption of interleukin-1 signaling improves the quality of wound healing. Am J Pathol 174:2129-36 |
| Daley, Jean M; Thomay, Alan A; Connolly, Michael D et al. (2008) Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J Leukoc Biol 83:64-70 |
| Xu, X Julia; Reichner, Jonathan S; Mastrofrancesco, Balduino et al. (2008) Prostaglandin E2 suppresses lipopolysaccharide-stimulated IFN-beta production. J Immunol 180:2125-31 |
| Lavigne, Liz M; O'Brien, Xian M; Kim, Minsoo et al. (2007) Integrin engagement mediates the human polymorphonuclear leukocyte response to a fungal pathogen-associated molecular pattern. J Immunol 178:7276-82 |
| Lavigne, Liz M; Albina, Jorge E; Reichner, Jonathan S (2006) Beta-glucan is a fungal determinant for adhesion-dependent human neutrophil functions. J Immunol 177:8667-75 |
| LeBlanc, Brian W; Albina, Jorge E; Reichner, Jonathan S (2006) The effect of PGG-beta-glucan on neutrophil chemotaxis in vivo. J Leukoc Biol 79:667-75 |
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