Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rats

doi:10.1016/0016-5085(95)90576-6

Gastroenterology

Volume 109, Issue 4, October 1995, Pages 1173-1180

https://doi.org/10.1016/0016-5085(95)90576-6 Get rights and content

Abstract

$Background & Aims$ : Arthritic patients are at greater risk of developing nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers than other NSAID users. Leukocyte adherence to the vascular endothelium has been suggested to play an important role in the pathogenesis of experimental NSAID-associated gastropathy. The aim of this study was to examine the role of leukocyte adherence in NSAID-induced gastric injury in healthy and adjuvant-induced arthritic rats. $Methods$ : Leukocyte adherence was examined using intravital microscopy before and after indomethacin administration. The role of CD18 and intercellular adhesion molecule 1 (ICAM-1) in indomethacin-induced gastric injury and leukocyte adherence was examined using specific monoclonal antibodies against these molecules. $Results$ : Indomethacin (5–10 mg/kg) caused significantly more gastric damage in arthritic than normal rats, and the former group had significantly greater levels of leukocyte adherence to mesenteric postcapillary venules under basal conditions. Dexamethasone markedly reduced basal and indomethacin-induced leukocyte adherence and the extent of gastric damage. In arthritic rats, pretreatment with a monoclonal antibody directed against ICAM-1 significantly reduced gastric damage and leukocyte adherence to the levels observed in healthy rats, whereas an antibody directed against CD18 had no effect. $Conclusions$ : Indomethacin-induced damage in healthy and arthritic rats is largely dependent on ICAM-1 expression. The increased susceptibility of arthritic rats to indomethacin-induced gastric injury may be partly related to elevated levels of ICAM-1-dependent leukocyte adherence.

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Hydrogen sulfide exerts a number of cytoprotective and anti-inflammatory effects in many organ systems. In an effort to exploit these potent and beneficial effects, a number of hydrogen sulfide-releasing derivatives of existing drugs have been developed and extensively tested in pre-clinical models. In particular, efforts have been made by several groups to develop hydrogen sulfide-releasing derivatives of a number of nonsteroidal anti-inflammatory drugs. The main goal of this approach is to reduce the gastrointestinal ulceration and bleeding caused by this class of drugs, particularly when used chronically such as in the treatment of arthritis. However, these drugs may also have utility for prevention of various types of cancer. This paper provides an overview of some of the mechanisms underlying the anti-inflammatory and cytoprotective actions of hydrogen sulfide. It also gives some examples of hydrogen sulfide-releasing anti-inflammatory drugs, and their actions in terms of reducing inflammation and attenuating the development of cancer in experimental models.
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^☆: Supported by a grant from the Medical Research Council of Canada (MRC). Dr. Wallace is an MRC Scientist and an Alberta Heritage Foundation for Medical Research (AHFMR) Scientist. Dr. McCafferty is an AHFMR Fellow.

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Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rats☆

Abstract

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Chromatogr

Trends Pharmacol Sci

Clin Immunol Immunopathol

J Biol Chem

Biochem Biophys Res Commun

Pharmacol Res

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

Nature New Biol

Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil dependent process

Am J Physiol

Aspirin-induced acute gastric mucosal injury is a neutrophil-dependent process in rats

Am J Physiol

Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury

Am J Physiol

Indomethacin-induced leukocyte adhesion in mesenteric venules: role of lipoxygenase products

Am J Physiol