Early pathogenic events in NSAID-induced gastrointestinal damage.
A number of studies show that the idea that inhibition of cyclooxygenase is the sole mechanism of NSAID-induced gastrointestinal damage is no longer tenable. We re-examined various aspects of the mechanism of small intestinal damage due to NSAIDs in rat. Subcellular organelle marker enzyme studies show selective alterations in mitochondrial and brush border marker enzymes. Electron microscopy shows changes compatible with uncoupling of mitochondrial oxidative phosphorylation. In vitro, all common acidic-NSAIDs (n = 15) were found to uncouple oxidative phosphorylation at concentrations (microM) easily achievable within intestinal epithelium. Experiments in bile duct ligated animals show that intact indomethacin within the gastrointestinal lumen is required for uncoupling. Relative importance and pathophysiological consequences of uncoupling and inhibition of cyclooxygenase were assessed following administration of R and S flurbiprofen: the former selectively uncouples whilst the latter is also an effective cyclooxygenase inhibitor. R flurbiprofen uncoupled in vitro and in vivo, increased intestinal permeability and caused mild intestinal inflammation, but had not significant effect on prostanoid levels and produced no ulcers. S flurbiprofen uncoupled and increased intestinal permeability equally but was associated with significant decreases in intestinal prostanoid levels, more inflammation and numerous ulcers. Collectively these studies suggest that uncoupling may underlie the "topical" phase of NSAID damage which leads to increased intestinal permeability and inflammation, but concomitant inhibition of cyclooxygenase is essential to drive the inflammation to ulcers.
Bjarnason
I
I
Department of Clinical Biochemistry, King's College School of Medicine and Dentistry, London, UK.
Hayllar
J
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D005767:Gastrointestinal Diseases / Q000139:chemically induced*; D007408:Intestinal Absorption / Q000187:drug effects; D008854:Microscopy, Electron; D008871:Microvilli / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors