Elderly Individuals are more suceptible to bacterial infection and these infections are a major cause of morbidity and mortality in hospitalized elderly patients. Research on the adaptive immune response has identified several age-associated defects in lymphocytes. Research on the innate response has been more sparse, focusing for the most part on the functional responsiveness of isolated resting macrophages and neutrophils to in vitro stimuli. The inflammatory response in young mice is a highly orchestrated sequence of events that entail sequential extravasation of neutrophils, monocytes and lymphocytes. The activities displayed by the macrophages and neutrophils are inflammatory, microbicidal and cytotoxic. Upon successful debridement of the wound, neutrophils apoptose and are phagocytized by macrophages and the macrophages, fibroblasts, and endothelial cells collaborate in wound resolution. If Th1 cells entering the site become activated, they will help sustain the inflammatory and cytotoxic activities of the macrophages. We hypothesize that age-associated deficiencies in inflammation may be associated with a loss of orchestration of these events rather than a loss of responsiveness of the cells of the innate immune system. To explore the validity of this hypothesis, we propose to examine the inflammatory response in young and aged mice using a model of intra-abdominal inflammation elicited by alum-precipitated egg albumin. To include T cells in the model, mice will receive, intravenously, activated, Th1-polarized OT-II ovalbumin-reactive T cells. The rate and degree of infiltration of neutrophils, macrophages and T cells will be monitored. Neutrophils will be analyzed ex vivo for expression of secretory vesicles and specific granules, expression of inflammatory cytokine and chemokine mRNA, and apoptosis and analyzed in vitro for phagocytosis, H2O2 production, and chemotaxis. Macrophages will be analyzed for expression of inflammatory and anti-inflammatory cytokine and chemokine mRNA, for expression of cell surface co-stimulatory molecules, and effective interaction with infiltrating T cells. This project will provide critical data on how advanced age impacts the inflammatory response and provide avenues of future study on means of therapeutic targeting of the deficiencies. Even transient improvement in inflammatory response will not only enhance microbial clearance and wound healing, but likely will also enhance the efficacy of vaccination against infectious disease. ? ? ?
