Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice.
OBJECTIVE
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 (FTVII(/-)) 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.
Beck
P L
PL
Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Xavier
R
R
Lu
N
N
Nanda
N N
NN
Dinauer
M
M
Podolsky
D K
DK
Seed
B
B
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004751:Enteritis / Q000139:chemically induced; D005647:Fucosyltransferases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D005753:Gastric Mucosa / Q000378:metabolism; D005756:Gastritis / Q000139:chemically induced; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000378:metabolism; D007213:Indomethacin; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009504:Neutrophils / Q000502:physiology; D010539:Permeability
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D005647:Fucosyltransferases; C031692:galactoside 3-fucosyltransferase; D007213:Indomethacin