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

Kimberly S. Kirkwood, Nigel W. Bunnett, John Maa, Ignazio Castagliolo, Bao Liu, Norma Gerard, Jeff Zacks, Charalabos Pothoulakis, Eileen F. Grady

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)G544-G551
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume281
Issue number2 44-2
DOIs
StatePublished - 2001

Keywords

  • Colitis
  • Neurogenic inflammation
  • Neurokinin-1 receptor
  • Substance P

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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