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O-038 Eosinophil-derived Protectin D1 Attenuates Acute Inflammation during Experimental Colitis

BACKGROUND: Eosinophils are constituents of the colonic mucosa during homeostasis and increase significantly during inflammation and disease states. While a number of studies suggest that eosinophils contribute to the pathogenesis of gastrointestinal inflammation, their role in intestinal health is not certain. AIM: We sought to define the impact of eosinophils in a mouse model of acute colitis to provide a greater understanding of the role(s) of these granulocytes during homeostasis. METHODS: Acute colitis was induced (DSS) in eosinophil competent wild type mice and in 3 models of mice deficient of eosinophils. Physical, histologic, cellular and molecular features were measured. Analysis of lipid mediators was completed in these cohorts and add-back experiments performed. RESULTS: Eosinophil-deficient (PHIL) mouse models developed significantly worse colitis than their eosinophil competent wild type (WT) counterparts (Disease Activity Index: 4.4 points greater day 6, P < 0.001; PHIL versus WT respectively). Eosinophil-deficient mice also succumbed to significantly greater mortality (PHIL–39% death rate versus WT–0% at 7 days). Upon harvest colon length was found to be significantly shorter (44.3 mm versus 53.9 mm, PHIL versus WT respectively; P < 0.001). Tissue injury was significantly greater in PHIL compared to WT DSS colitis challenged mice, as evidenced by histological scoring of ulceration, edema and leukocytic infiltration (19.5 versus 12.1, PHIL versus WT respectively; P < 0.001). Mice experimentally deficient in eosinophils by antibody mediated depletion (TRFK5) or by bone marrow transplantation (PHIL donor into WT recipients) were also found to develop significantly worse clinical and histological measures of colitis. Further analysis revealed a predominance of neutrophils in eosinophil-deficient mice (76.4% versus 45.7%, PHIL versus WT respectively; P < 0.05) and a significantly greater production of pro-inflammatory cytokines in inflamed PHIL versus WT colons (TNF-&agr; [2 fold, P < 0.05], IL-1&bgr; [2.9 fold, P < 0.01], IL-6 [3 fold, P < 0.05], and inducible NO synthase [2 fold, P < 0.05]). Lipidomic array of colonic tissue identified a deficiency in protectin D1 in mice deficient in eosinophils (11.1 versus 1.0 ng/g colon, PHIL versus WT respectively, P < 0.0001). Reconstitution of eosinophil-deficient mice with exogenous protectin D1 led to significant decrease of histological scores of colitic inflammation (9.4 versus 16.5, PD1 treated PHIL versus untreated PHIL respectively, P < 0.01) as well as attenuated neutrophil infiltration (54.6% versus 74.5%, PD1 treated PHIL versus untreated PHIL respectively; P < 0.01) and reduced expression of TNF-&agr; (0.7 fold, P < 0.05), IL-1&bgr; (0.3 fold, P < 0.05), IL-6 (0.3 fold, P < 0.05), and inducible NO synthase (0.7 fold, P < 0.05). CONCLUSION: These studies demonstrate that eosinophils exert a protective role in acute mouse colitis through the production of the anti-inflammatory lipid mediator protectin D1.