Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice

Citation
Pl. Beck et al., Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice, GASTROENTY, 119(3), 2000, pp. 699-705
Citations number
37
Categorie Soggetti
Gastroenerology and Hepatology","da verificare
Journal title
GASTROENTEROLOGY
ISSN journal
00165085 → ACNP
Volume
119
Issue
3
Year of publication
2000
Pages
699 - 705
Database
ISI
SICI code
0016-5085(200009)119:3<699:MONGID>2.0.ZU;2-V
Abstract
Background & Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) are common ly used agents that have a high incidence of gastrointestinal side effects resulting in significant morbidity and mortality. Leukocytes have been impl icated in NSAID-induced injury, but the mechanisms are unclear. We establis hed a murine model of NSAID-induced gastrointestinal damage to assess the r oles of candidate gene products in the pathogenesis of this injury. Methods : Indomethacin-induced gastrointestinal injury was assessed in wild-type an d several mutant murine lines, Leukocyte involvement was assessed by neutro phil depletion, impairment of recruitment (resulting from targeted disrupti on of fucosyltransferase VII [FTVII]), and the absence of mature T and B ce lls with the use of Rag 2(-/-) mice. Activation and oxygen free radicals we re assessed using gp91(phox-/-) mice that exhibit normal leukocyte recruitm ent but are deficient in myeloid cell activation and oxygen free radical ge neration, Results: impairment of leukocyte recruitment (FTVII/(-)) and neut rophil depletion resulted in more than a 50% reduction in NSAID-induced inj ury. However, mice deficient in mature T and B cells had NSAID-induced dama ge comparable to control mice. Leukocyte activation was required for NSAID- induced damage because the gp91(phox-/-) mice were less susceptible to NSAI D injury than wild-type mice. Conclusions: In this murine model system, FTV II-dependent leukocyte recruitment, leukocyte activation via gp91(phox), an d neutrophils are required for NSAID-induced gastrointestinal injury, where as T and B cells are not essential.