Abstract
We examined whether extraintestinal manifestations of granulomatous enterocolitis in rabbits might be produced by the long-term administration of muramyl dipeptide which represents the basic fragment of the bacterial cell wall, emulsified with Freund's incomplete adjuvant. Muramyl dipeptide emulsion was injected submucosally at six sites in the rectum and colon, 10 cm proximal to the anus, each time with a flexible endoscope. Seven rabbits were injected nine times or more every month, and all were sacrificed 1 month after the last injection. The histological changes in the colon in the seven rabbits were mononuclear cell infiltration, epithelioid granulomas, granulomatous lesion, and denuded and regenerative epithelia, although the changes differed in degree. In five of the seven rabbits, histological examination of the liver showed pericholangitis and periductal fibrosis, findings analogous to sclerosing cholangitis in patients with inflammatory bowel disease. In four of the seven rabbits, fibrosis bridging mainly between portal and portal veins, and, in places, between portal and central veins, was seen. Two of the seven rabbits developed polyarthritis. The histological changes in our model suggest that continuous stimulation with bacterial cell wall fragments may be involved in the extraintestinal manifestations of chronic intestinal inflammation such as that seen in inflammatory bowel disease.
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Kuroe K, Haga Y, Funakoshi O, et al. Rabbit granulomatous enterocolitis induced by injection of muramyl dipeptide emulsified with Freund's incomplete adjuvant. J Gastroenterol 1995;30: 472–477.
Reichert CM, Carelli C, Jolivet M, et al. Synthesis of conjugates containing N-acetylmuramyl-l-alanyl-d-isoglutaminyl (MDP). Their use as hapten-carrier systems. Mol Immunol 1980;17: 357–363.
Bahr GM, Carelli C, Audibert F, et al. Analysis of the antigenic relationship of various derivatives of N-acetyl-muramyl-l-ala-d-isoglutamine (MDP), using anti-MDP antibodies. Mol Immunol 1982;19:737–745.
Chedid L, Parant M, Parant F, et al. Enhancement of certain biological activities of muramyl dipeptide derivatives after conjugation to a multi-poly(Dl-alanine)-poly(l-lysine) carrier. Proc Natl Acad Sci USA 1979;76:6557–6561.
Nydegger UE, Svehag S-E. Improved standarization in the quantitative estimation of soluble immune complexes making use of an international reference preparation. Results of a collaborative multicentre study. Clin Exp Immunol 1984;58:502–509.
Sackett DL, Haynes RB, Tugwell P. Clinical epidemiology. 1st Ed. Boston: Little, Brown, 1985;106–107.
Sartor RB, Cromartie WJ, Powell DW, et al. Granulomatous enterocolitis induced in rats by purified bacterial cell wall fragments. Gastroenterology 1985;89:587–595.
Zimmermann EM, Sartor RB, McCall RD, et al. Insulin-like growth factor I and interleukin 1β messenger RNA in a rat model of granulomatous enterocolitis and hepatitis. Gastroenterology 1993;105:399–409.
Emori K, Tanaka A. Granuloma formation by synthetic bacteria cell wall fragment: Muramyl dipeptide. Infect immun 1978; 19:613–620.
Tanaka A, Emori K. Epithelioid granuloma formation by a synthetic bacterial cell wall component, muramyl dipeptide (MDP). Am J Pathol 1980;98:733–748.
Emori K, Nagao S, Shigematsu N, et al. Granuloma formation by muramyl dipeptide associated with branched fatty acids, a structure probably essential for tubercle formation byMycobacterium tuberculosis. Infect Immun 1985;49:244–249.
Kono K, Ohnishi K, Omata M, et al. Experimental portal fibrosis produced by intraportal injection of killed nonpathogenicEscherichia coli in rabbits. Gastroenterology 1988;94:787–796.
Hobson CH, Butt TJ, Ferry DM, et al. Enterohepatic circulation of bacterial chemotactic peptide in rats with experimental colitis. Gastroenterology 1988;94:1006–1013.
Yamada S, Ishii M, Liang LS, et al. Small duct cholangitis induced by N-formyll-methioninel-leucinel-tyrosine in rats. J Gastroenterol 1994;29:631–636.
Carter RL, Jamison DG, Vollum RL. Histological changes evoked in mice by Freund's incomplete adjuvant. J Pathol Bacteriol 1968;95:471–476.
Yamanaka M, Hiromatsu K, Hirahara T, et al. Pathological studies on local tissue reactions in guinea pigs and rats caused by four different adjuvants. J Vet Med Sci 1992;54:685–692.
Kohashi O, Aihara K, Ozawa A, et al. New model of a synthetic adjuvant, N-acetylmuramyl-l-alanyl-d-isoglutamine-induced arthritis. Lab Invest 1982;47:27–36.
Chang Y, Pearson CM, Chedid L. Adjuvant polyarthritis. V. Induction by N-acetylmuramyl-l-alanyl-d-isoglutamine, the smallest peptide subunit of bacterial peptidoglycan. J Exp Med 1981;153:1021–1026.
Pearson CM. Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol Med 1956;91:95–101.
Chapman RWG, Marborgh BÅ, Rhodes JM, et al. Primary sclerosing cholangitis: A review of its clinical features, cholangiography, and hepatic histology. Gut 1980;21:870–877.
Zauli D, Schrumpf E, Crespi C, et al. An autoantibody profile in primary sclerosing cholangitis. J Hepatol 1987;5:14–18.
McEwen C, Lingg C, Kirsner JB, et al. Arthritis accompanying ulcerative colitis. Am J Med 1962;33:923–941.
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Kuroe, K., Haga, Y., Funakoshi, O. et al. Extraintestinal manifestations of granulomatous enterocolitis induced in rabbits by long-term submucosal administration of muramyl dipeptide emulsified with Freund's incomplete adjuvant. J Gastroenterol 31, 199–206 (1996). https://doi.org/10.1007/BF02389518
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DOI: https://doi.org/10.1007/BF02389518