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Gut 49:443-453 doi:10.1136/gut.49.3.443
  • Review

Cyclooxygenase 2—implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives

  1. F HALTER,
  2. A S TARNAWSKI
  1. VA Medical Center, Long Beach
  2. University of California Irvine, California, USA
  3. Gastrointestinal Unit, University of Berne
  4. Inselspital, Berne, Switzerland
  5. Department of Experimental Clinical Medicine
  6. Ruhr-University, Bochum, Germany
  1. 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
  1. A SCHMASSMANN
  1. VA Medical Center, Long Beach
  2. University of California Irvine, California, USA
  3. Gastrointestinal Unit, University of Berne
  4. Inselspital, Berne, Switzerland
  5. Department of Experimental Clinical Medicine
  6. Ruhr-University, Bochum, Germany
  1. 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
  1. B M PESKAR
  1. VA Medical Center, Long Beach
  2. University of California Irvine, California, USA
  3. Gastrointestinal Unit, University of Berne
  4. Inselspital, Berne, Switzerland
  5. Department of Experimental Clinical Medicine
  6. Ruhr-University, Bochum, Germany
  1. 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

    Abstract

    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.

    Footnotes

    • Abbreviations used in this paper:
      COX
      cyclooxygenase
      NSAID
      non-steroidal anti-inflammatory drug
      PGE2
      prostaglandin E2
      NO
      nitric oxide
      bFGF
      basic fibroblast growth factor
      BrdU
      bromodeoxyuridine
      ERK-2
      extracellular signal regulated kinase 2