Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice
| Autor: | Nanthakumar N. Nanda, Mary C. Dinauer, Ramnik J. Xavier, Naifang Lu, Brian Seed, Daniel K. Podolsky, Paul L. Beck |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Fucosyltransferase Ratón Gastrointestinal Diseases Neutrophils Indomethacin Permeability Cell Line Lesion Pathogenesis Mice Chronic granulomatous disease Intestine Small medicine Leukocytes Animals Intestinal Mucosa Mice Knockout NADPH oxidase Membrane Glycoproteins Hepatology biology Anti-Inflammatory Agents Non-Steroidal Gastroenterology NADPH Oxidases medicine.disease Fucosyltransferases Pathophysiology Enteritis DNA-Binding Proteins Mice Inbred C57BL Gastric Mucosa Gastritis Immunology NADPH Oxidase 2 biology.protein Cyclooxygenase medicine.symptom |
| Zdroj: | Gastroenterology. 119(3) |
| ISSN: | 0016-5085 |
| Popis: | Background & 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 (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. GASTROENTEROLOGY 2000;119:699-705 |
| Databáze: | OpenAIRE |
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