Role of Macrophage and Matrix Metallproteinases in Experimental Enterpathy in Rats

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Backgraund & Aims. Intrarectal administration of indomethacin (Indo) induces longitudinal ulcers of the small intestine in rats which are similar to those in Crohn's desease. Previously, we reported that lipopolysaccharide from intestinal flora played a central role in this experimental enteropathy. The aims of this study are to elucidate the role of macrophage, macrophathy in rats. Materials. Methods & Results. In male wistar rats weighing 190-220g, enteropathy was inducted by intracolonic administration of 24 mg/kg of Indo. Intraperitoneal administration of liposomes containing dichloromethylene bisphosphonate (Cl_2MBP) resulted in marked depletion of macrophages in the small intestine. In this macrophage-depleted rat, small intestinal damage strikingly decreased to 22%. Administration of anti- TNF- α, IL- 1 β, and IL- 6 antibodies significantly ameliorated Indo enteropathy in a dose- dependent fashion. Inhibition of enteropathy by a combination of the three antibodies reached up to 87.5%, which was equal to that in macrophage- depleted rats. Additional administration of recombinant proinflammatory cytokines restored Indo enteropathy in macrophage- depleted rats. The small intestinal damage was serially observed 3, 6, 12, 24 hours, 3, and 7 days after Indo administration. The peak of the damage was at 24 hours. Then, we investigated serial changes in MMP-2, -3, and -9 activities in Indo enteropathy. Administration of the broad- spectrum MMPs inhibitor GM6001 ameliorated Indo enteropathy in a dose- dependent fashion. Conclusions. Our results clarified that macrophages played an important role in Indo enteropathy in rats via production of proinflammatory cytokines and MMPs