Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice

Paul L. Beck, Ramnik Xavier, Naifang Lu, Nanthakumar N. Nanda, Mary Dinauer, Daniel K. Podolsky, Brian Seed

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Background and Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used agents that have a high incidence of gastrointestinal side effects resulting in significant morbidity and mortality. Leukocytes have been implicated in NSAID-induced injury, but the mechanisms are unclear. We established a murine model of NSAID-induced gastrointestinal damage to assess the roles of candidate gene products in the pathogenesis of this injury. Methods: Indomethacin-induced gastrointestinal injury was assessed in wild-type and several mutant murine lines. Leukocyte involvement was assessed by neutrophil depletion, impairment of recruitment (resulting from targeted disruption of fucosyltransferase VII [FTVII]), and the absence of mature T and B cells with the use of Rag 2-(/)- mice. Activation and oxygen free radicals were assessed using gp91(phox(-(/)- mice that exhibit normal leukocyte recruitment but are deficient in myeloid cell activation and oxygen free radical generation. Results: Impairment of leukocyte recruitment (FT-VII(/)-) and neutrophil depletion resulted in more than a 50% reduction in NSAID-induced injury. However, mice deficient in mature T and B cells had NSAID-induced damage comparable to control mice. Leukocyte activation was required for NSAID-induced damage because the gp91(phox)-(/)- mice were less susceptible to NSAID injury than wild-type mice. Conclusions: In this murine model system, FTVII-dependent leukocyte recruitment, leukocyte activation via gp91(phox), and neutrophils are required for NSAID-induced gastrointestinal injury, whereas T and B cells are not essential.

Original languageEnglish (US)
Pages (from-to)699-705
Number of pages7
JournalGastroenterology
Volume119
Issue number3
DOIs
StatePublished - 2000

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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