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implications on maintenance of gastric mucosal
integrity and ulcer healing: controversial issues and
perspectives
VA Medical Center, Long Beach
University of California Irvine, California, USA
A SCHMASSMANN
Gastrointestinal Unit, University of Berne
Inselspital, Berne, Switzerland
B M PESKAR
Department of Experimental Clinical Medicine
Ruhr-University, Bochum, Germany
Correspondence to: Dr F Halter, or Dr A S Tarnawski, Gastroenterology Section (111G), DVA Medical Center, Long Beach, CA 5901 E Seventh Street, Long Beach, CA 90822, USA. Fhalter{at}freesurf.ch or atarnawski{at}yahoo.com
Cyclooxygenase (COX), the key enzyme for synthesis of
prostaglandins, exists in two isoforms (COX-1 and COX-2). COX-1 is
constitutively expressed in the gastrointestinal tract in large
quantities and has been suggested to maintain mucosal integrity through
continuous generation of prostaglandins. COX-2 is induced predominantly
during inflammation. On this premise selective COX-2 inhibitors not
affecting COX-1 in the gastrointestinal tract mucosa have been
developed as gastrointestinal sparing anti-inflammatory drugs. They
appear to be well tolerated by experimental animals and humans
following acute and chronic (three or more months) administration.
However, there is increasing evidence that COX-2 has a greater
physiological role than merely mediating pain and inflammation. Thus
gastric and intestinal lesions do not develop when COX-1 is inhibited but only when the activity of both COX-1 and COX-2 is suppressed. Selective COX-2 inhibitors delay the healing of experimental gastric ulcers to the same extent as non-COX-2 specific non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, when given chronically to
experimental animals, they can activate experimental colitis and cause
intestinal perforation. The direct involvement of COX-2 in ulcer
healing has been supported by observations that expression of COX-2
mRNA and protein is upregulated at the ulcer margin in a temporal and
spatial relation to enhanced epithelial cell proliferation and
increased expression of growth factors. Moreover, there is increasing
evidence that upregulation of COX-2 mRNA and protein occurs during
exposure of the gastric mucosa to noxious agents or to
ischaemia-reperfusion. These observations support the concept that
COX-2 represents (in addition to COX-1) a further line of defence for
the gastrointestinal mucosa necessary for maintenance of mucosal
integrity and ulcer healing.
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