Essential role of macrophages and macrophage-related proinflammatory cytokines in indomethacin-induced enteropathy in rats *
[Introduction] Intrarectal administration of indomethacin induces longitudinal ulcers of the small intestine in rats similar to those in Crohn's disease. A recent study reported that lipopolysaccharide from intestinal flora played a central role in this experimental enteropathy. [Aims & Methods] The aim of this study was to investigate the role of macrophages in indomethacin-induced enteropathy. In the first experiment, male Wistar rats were intraperitoneally given liposomes containing 50, 200 or 400 mg/kg of dichloromethylene-bisphosphonate (C12MBP ), which is known to injure macrophages. Four days after the C12MBP-liposome administration, the number of macrophages in the small intestine was evaluated by the immunohistochemical method. In the second experiment, the rats administered 400 mg/kg of C12MBP-liposomes were intrarectally given 24 mg/kg of indomethacin. In the third experiment, the conventional Wistar rats were intraperitoneally given anti-cytokine neutralizing antibodies against tumor necrosis factor-a (TNF-α), interleukin-6 (IL-6) and interleukin-lβ (IL-1β) before indomethacin administration. In the fourth experiment, after administration of C12MBP-liposomes, the macrophage-depleted rats were given recombinant rat TNF-α, IL-6 and IL-1β before indomethacin administration. In all experiments except the first one, small intestinal damage was macroscopically and histologically assessed 24 hours after indomethacin administration. [Results] In all the rats administered C12MBP-liposomes, depletion of macrophages in the small intestine was observed. Indomethacin-induced small intestinal damage in these macrophage-depleted rats strikingly decreased to 19.6%. Administration of anti-TNF-α, IL-6 and IL-1β neutralizing antibodies significantly ameliorated indomethacin 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 the macrophage-depleted rats. Additional administration of recombinant rat proinflammatory cytokines restored indomethacin enteropathy in the macrophage-depleted rats. [Conclusions] The results indicated that macrophages play an important role in indomethacin enteropathy in rats via the production of proinflammatory cytokines. (Accepted on October 24, 2002) Kawasaki Igakkaishi 28 (4 ) : 243-256, 2002
