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.