Intestinal permeability in the pathogenesis of NSAID-induced enteropathy
The pathogenesis of nonsteroidal antiinflammatory drug (NSAID)-induced small bowel disease suggests that increased intestinal permeability is the central mechanism that translates biochemical damage to tissue damage. The purpose of this review is to summarize studies on the effect of NSAIDs to increase intestinal permeability in humans and methods for limiting this effect.
A Medline search was made for papers that described measurements of increased intestinal permeability in humans.
Virtually all studies agree that all conventional NSAIDs increase intestinal permeability in the human within 24 h of ingestion and that this is equally evident when they are taken long term. Various methods have been tried to limit the damage. The most promising agents are coadministration of synthetic prostaglandins, micronutrients, pre-NSAIDs, and COX-2 selective agents. However, their efficacy in preventing the development of NSAID enteropathy in the long term has not been studied in detail, and, in the case of COX-2 selective agents, small bowel damage is comparable to that which is seen with conventional NSAIDs.
NSAID enteropathy is associated with significant morbidity and occasionally mortality. There are no proven effective ways of preventing this damage. Because increased intestinal permeability appears to be a central mechanism in the pathogenesis of NSAID enteropathy, it becomes a potential therapeutic target for prevention. At present there are a number of ways to limit the increased permeability, but additional studies are required to assess if this approach reduces the prevalence and severity of NSAID enteropathy.
Key wordsNSAIDs intestinal toxicity intestinal inflammation intestinal permeability
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- 1.Tympner F. Gastroscopic findings after therapy with nonsteroidal anti-inflammatory drugs. J Rheumatol 1981;40:179–181.Google Scholar
- 6.Lakari EN, Lacey Smith J, Lidsky MD, Graham DY. Gastroduodenal damage and dyspeptic symptoms in arthritis patients during chronic nonsteroidal anti-inflammatory drug use. Am J Gastroenterol 1987;82:1153–1158.Google Scholar
- 18.Vane JR, Botting RM. Overview: mechanisms of action of antiinflammatory drugs. In: Vane J, Botting J, Botting R, editors. Improved non-steroidal anti-inflammatory drugs. COX-2 enzyme inhibitors. Dordrecht: Kluwer; 1996.1–27.Google Scholar
- 22.Somasundaram S, Macpherson AJ, Hayllar J, Saratchandra P, Bjarnason I. Enterocyte mitochondrial damage due to NSAID in the rat. Gut 1992;33(suppl 1):S5.Google Scholar
- 23.Somasundaram S, Sadique J. The effect of peripheral inflammation and the action of anti-inflammatories on the intestinal transport of l4C-leucine in rats. Acta Biol Med Exp 1985;10:35–39.Google Scholar
- 26.Somasundaram S, Sigthorsson G, Price AB, Tavares IA, Rafi S, Mahmud T, et al. The relative importance of inhibition of cyclooxygenase and uncoupling of oxidative phosphorylation in the gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2000;14:639–650.PubMedCrossRefGoogle Scholar
- 31.Melrange R, Moore G, Blower PR, Coates ME, Ward FW, Ronaasen V. A comparison of indomethacin with ibuprofen on gastrointestinal mucosal integrity in conventional and germ free rats. Aliment Pharmacol Ther 1992;6:67–77.Google Scholar
- 32.Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action of aspirin-like drugs. Nature (Lond) 1971;231:232–235.Google Scholar
- 40.Maiden L, Thjodleifsson B, Seigal A, Bjarnason II, Scott D, Birgisson S, et al. Long-term effects of nonsteroidal antiinflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol 2007;5:1040–1045.PubMedCrossRefGoogle Scholar
- 44.Gullikson GW, Sender M, Bass P. Laxative-like effects of nonsteroidal anti-inflammatory drugs on intestinal fluid movement and membrane integrity. J Pharmacol Exp Ther 1981;220:236–252.Google Scholar
- 45.Lichtenberger LM, Romero JJ, Wang ZM. ASA forms an ionic complex with phosphatidylcholine: possible molecular explanation for its ulcerogenic action. Gastroenterology 1994;106:A134.Google Scholar
- 46.Lichtenberger LM, Wang Z-M, Romero JJ, Ulloa C, Perez JC, Giraud M-N, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury. Nat Med 1995;1:154–158.PubMedCrossRefGoogle Scholar
- 52.Rafi S. Studies on the pathogenesis of NSAID enteropathy, with special reference to mitochondria. PhD thesis. London: University of London. 1999.Google Scholar
- 53.Hotz-Behofsits C, Walley M, Sigthorsson G, Simpson R, Bjarnasson I. NSAID enteropathy with normal mucosal prostaglandins. Gastroenterology 2004;126 17 Suppl S417.Google Scholar
- 69.Aabakken L, Larsen S, Osnes M. Cimetidine tablets or suspension in the prevention of gastrointestinal mucosal lesions caused by nonsteroidal anti-inflammatory drugs. Scand J Rheumatol 1989;18:647–655.Google Scholar
- 71.Shah AA, Thjodleifsson B, Murray FE, Sigthorsson G, Oddson E, Gudjonsson H, et al. A randomised, double blind, double dummy, crossover study of the effects of nimesulide and naproxen on the gastrointestinal tract and an in vivo assessment of their selectivity for cyclooxygenase 1 and 2. Gut 2001;48:339–348.PubMedCrossRefGoogle Scholar
- 86.Bours MJ, Bos HJ, Meddings JB, Brummer RJ, van den Brandt PA, Dagnelie PC. Effects of oral adenosine 5′-triphosphate and adenosine in enteric-coated capsules on indomethacin-induced permeability changes in the human small intestine: a randomized cross-over study. BMC Gastroenterol 2007;7:23.PubMedCrossRefGoogle Scholar