title: Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat.
abstract: BACKGROUND
  The pathogenesis of NSAID-induced gastrointestinal damage is believed to involve a nonprostaglandin dependent effect as well as prostaglandin dependent effects. One suggestion is that the nonprostaglandin mechanism involves uncoupling of mitochondrial oxidative phosphorylation.
  
  
  OBJECTIVE
  To assess the role of uncoupling of mitochondrial oxidative phosphorylation in the pathogenesis of small intestinal damage in the rat.
  
  
  METHODS
  We compared key pathophysiologic events in the small bowel following (i) dinitrophenol, an uncoupling agent (ii) parenteral aspirin, to inhibit cyclooxygenase without causing a 'topical' effect and (iii) the two together, using (iv) indomethacin as a positive control.
  
  
  RESULTS
  Dinitrophenol altered intestinal mitochondrial morphology, increased intestinal permeability and caused inflammation without affecting gastric permeability or intestinal prostanoid levels. Parenteral aspirin decreased mucosal prostanoids without affecting intestinal mitochondria in vivo, gastric or intestinal permeability. Aspirin caused no inflammation or ulcers. When dinitrophenol and aspirin were given together the changes in intestinal mitochondrial morphology, permeability, inflammation and prostanoid levels and the macro- and microscopic appearances of intestinal ulcers were similar to indomethacin.
  
  
  CONCLUSIONS
  These studies allow dissociation of the contribution and consequences of uncoupling of mitochondrial oxidative phosphorylation and cyclooxygenase inhibition in the pathophysiology of NSAID enteropathy. While uncoupling of enterocyte mitochondrial oxidative phosphorylation leads to increased intestinal permeability and low grade inflammation, concurrent decreases in mucosal prostanoids appear to be important in the development of ulcers.
authors.affiliation: Departments of Medicine and Surgery, Guy's, King's and St Thomas' Medical School, Camberwell, UK.
authors.forename: S
authors.initials: S
authors.lastname: Somasundaram
authors.forename: G
authors.initials: G
authors.lastname: Sigthorsson
authors.forename: R J
authors.initials: RJ
authors.lastname: Simpson
authors.forename: J
authors.initials: J
authors.lastname: Watts
authors.forename: M
authors.initials: M
authors.lastname: Jacob
authors.forename: I A
authors.initials: IA
authors.lastname: Tavares
authors.forename: S
authors.initials: S
authors.lastname: Rafi
authors.forename: A
authors.initials: A
authors.lastname: Roseth
authors.forename: R
authors.initials: R
authors.lastname: Foster
authors.forename: A B
authors.initials: AB
authors.lastname: Price
authors.forename: J M
authors.initials: JM
authors.lastname: Wrigglesworth
authors.forename: I
authors.initials: I
authors.lastname: Bjarnason
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D004386:Duodenum / Q000502:physiology; D020895:Enterocytes / Q000166:cytology / Q000502:physiology; D007408:Intestinal Absorption; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000502:physiology*; D010085:Oxidative Phosphorylation; D010086:Oxidative Phosphorylation Coupling Factors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010086:Oxidative Phosphorylation Coupling Factors; D011453:Prostaglandins; D014475:Uncoupling Agents; D011451:Prostaglandin-Endoperoxide Synthases