This project is designed to test the hypothesis that cell wall polymers derived from intestinal bacteria are involved in the pathogenesis of Crohn's disease by producing self-perpetuating acute and chronic granulomatous inflammation leading to fibrosis in the distal intestine of susceptible hosts. Peptidoglycan- polysaccharide complexes and lipopolysaccharide (endotoxin) are present in high concentrations within the distal intestinal lumen and have potent inflammatory and immunomodulating properties. Cell wall polymers produce chronic, spontaneously reactivating experimental granulomatous enterocolitis after direct injection: and arthritis, liver disease, uveitis, anemia and cutaneous vasculitis following systemic injection. The inflammatory response, distribution of systemic inflammation and immunological sequelae of cell wall polymers in animal models resemble those seen in Crohn's disease. lead!n: to our hypothesis that these ubiquitous bacterial cell wall polymers are responsible for the induction and perpetuation of the local and systemic manifestations of Crohn's disease. The differential response between inbred rat strains to cell wall polymer-induced enterocolitis emphasizes the importance of genetic host susceptibility to these natural occurring luminal constituents.
The specific aims of this proposal are to: 1) investigate the pathogenesis and modulation of experimental granulomatous enterocolitis induced by intramural injection of cell wall polymers derived from enteric bacteria. 2) determine if cell wall polymers from the lumen can induce and perpetuate intestinal inflammation. 3) investigate the ability of parenterally injected cell wall polymers and inflammatory mediators to reactivate peptidoglycan- polysaccharide-induced enterocolitis. and 4) determine whether in vivo exposure to luminal cell wall polymers influences the state of activation of intestinal mucosal macrophages. These investigations will refine an experimental animal model of Crohn's disease, examine the role of cytokines in its pathogenesis, and explore host factors determining the severity and chronicity of inflammatory response. This animal model of Crohn's disease is unique in that chronic granulomatous inflammation is induced by bacterial products normally present in high concentrations within the distal intestines, spontaneous reactivation and remissions occur, genetic susceptibility determines the course of inflammation, and extraintestinal disease accompanies the locally induced intestinal inflammation.
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