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Am J Physiol Gastrointest Liver Physiol 281: G544-G551, 2001;
0193-1857/01 $5.00
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Vol. 281, Issue 2, G544-G551, August 2001

Deletion of neutral endopeptidase exacerbates intestinal inflammation induced by Clostridium difficile toxin A

Kimberly S. Kirkwood1, Nigel W. Bunnett1,2, John Maa1, Ignazio Castagliolo3, Bao Liu4, Norma Gerard4, Jeff Zacks4, Charalabos Pothoulakis3, and Eileen F. Grady1

Departments of 1 Surgery and 2 Physiology, University of California, San Francisco, California 94143; 3 Division of Gastroenterology, Beth Israel Deaconess Medical Center, and Pulmonary Division Ina Sue Pelmutter Laboratory, Children's Hospital, Harvard Medical School, Boston 02115; and 4 Department of Pathology, Boston University School of Medicine, Boston, Massachusetts 02118

Toxin A (TxA) of Clostridium difficile induces acute inflammation of the intestine initiated by release of substance P (SP) and activation of the neurokinin-1 receptor. However, the mechanisms that terminate this response are unknown. We determined whether the SP-degrading enzyme neutral endopeptidase (NEP, EC 3.4.24.11) terminates TxA-induced enteritis. We used both genetic deletion and pharmacological inhibition of NEP to test this hypothesis. In wild-type mice, instillation of TxA (0.5-5 µg) into ileal loops for 3 h dose dependently increased ileal fluid secretion, stimulated granulocyte transmigration determined by myeloperoxidase activity, and caused histological damage characterized by depletion of enterocytes, edema, and neutrophil accumulation. Deletion of NEP reduced the threshold secretory and inflammatory dose of TxA and exacerbated the inflammatory responses by more than twofold. This exacerbated inflammation was prevented by pretreatment with recombinant NEP. Conversely, pretreatment of wild-type mice with the NEP inhibitor phosphoramidon exacerbated enteritis. Thus NEP terminates enteritis induced by C. difficile TxA, underlying the importance of SP degradation in limiting neurogenic inflammation.

substance P; neurokinin-1 receptor; neurogenic inflammation; colitis


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