Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have as a common side effect the ability to damage the lining of the intestine. Since NSAIDs inhibit prostanoid biosynthesis, it is accepted that the gastric complications reflect a protective role of some prostaglandins in suppressing intestinal inflammation and damage. Still, the identity of the relevant prostaglandins has not been known, and the involvement of multiple prostaglandin receptors in this beneficial response could not be excluded. Now, however, Kabashima et al. provide a surprisingly simple answer. Taking advantage of the many mouse knockout strains available that lack one or another of the prostaglandin receptors, they show that the prostaglandin PGE2, acting through a single receptor, EP4, is largely if not single-handedly responsible for maintaining the integrity of the intestinal mucosa. While EP4-deficient mice do not ordinarily show symptoms of colitis, the authors find that they are hypersensitive to damage by low doses of the proinflammatory compound dextran sodium sulfate-- doses that are well tolerated by wild-type mice and by animals with mutations in the other receptor genes. Conversely, NSAID treatment, coupled with low-dose DSS, can cause acute disease even in wild-type mice, but treatment with a specific EP4 agonist prevents this response. Hence, this class of agonist might be useful in protecting humans from NSAID gastrotoxicity and might also prove beneficial for ulcerative colitis and Crohn disease, conditions where the gastric mucosa is prone to inflammation and tissue damage.

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Contact: John Ashkenas
scied@the-jci.org
416-946-7593
Journal of Clinical Investigation
27-Mar-2002

Page: 1
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