Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat

Background: The pathogenesis of NSAID-induced gastrointestinal damage is be lieved to involve a nonprostaglandin dependent effect as well as prostaglan din dependent effects. One suggestion is that the nonprostaglandin mechanis m involves uncoupling of mitochondrial oxidative phosphorylation. Aims: To assess the role of uncoupling of mitochondrial oxidative phosphory lation in the pathogenesis of small intestinal damage in the rat. Methods: We compared key pathophysiologic events in the small bowel followi ng (i) dinitrophenol, an uncoupling agent (ii) parenteral aspirin, to inhib it cyclooxygenase without causing a 'topical' effect and (iii) the two toge ther, using (iv) indomethacin as a positive control. Results: Dinitrophenol altered intestinal mitochondrial morphology, increas ed intestinal permeability and caused inflammation without affecting gastri c permeability or intestinal prostanoid levels. Parenteral aspirin decrease d mucosal prostanoids without affecting intestinal mitochondria in vivo, ga stric or intestinal permeability. Aspirin caused no inflammation or ulcers. When dinitrophenol and aspirin were given together the changes in intestin al mitochondrial morphology, permeability, inflammation and prostanoid leve ls and the macro- and microscopic appearances of intestinal ulcers were sim ilar to indomethacin. Conclusions: These studies allow dissociation of the contribution and conse quences of uncoupling of mitochondrial oxidative phosphorylation and cycloo xygenase inhibition in the pathophysiology of NSAID enteropathy. While unco upling of enterocyte mitochondrial oxidative phosphorylation leads to incre ased intestinal permeability and low grade inflammation, concurrent decreas es in mucosal prostanoids appear to be important in the development of ulce rs.