This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Baatar, D. Articles by Tarnawski, A. S. Search for Related Content PubMed PubMed Citation Articles by Baatar, D. Articles by Tarnawski, A. S.

(American Journal of Pathology. 2002;160:963-972.)
© 2002 American Society for Investigative Pathology

Regular Articles

Selective Cyclooxygenase-2 Blocker Delays Healing of Esophageal Ulcers in Rats and Inhibits Ulceration-Triggered c-Met/Hepatocyte Growth Factor Receptor Induction and Extracellular Signal-Regulated Kinase 2 Activation

Dolgor Baatar^*, Michael K. Jones, Rama Pai, Hirofumi Kawanaka, Imre L. Szabo, Woo S. Moon, Seigo Kitano^* and Andrzej S. Tarnawski

From the Department of Veterans Affairs MedicalCenter,
Long Beach, California; the Universityof California,
Irvine, California; andthe Department of Surgery I,^*
Oita Medical University, Oita, Japan

Nonsteroidal anti-inflammatory drugs, both nonselective and cyclooxygenase-2 (COX-2) selective, delay gastric ulcer healing. Whether they affect esophageal ulcer healing remains unexplored. We studied the effects of the COX-2 selective inhibitor, celecoxib, on esophageal ulcer healing as well as on the cellular and molecular events involved in the healing process. Esophageal ulcers were induced in rats by focal application of acetic acid. Rats with esophageal ulcers were treated intragastrically with either celecoxib (10 mg/kg, once daily) or vehicle for 2 or 4 days. Esophageal ulceration triggered increases in: esophageal epithelial cell proliferation; expression of COX-2 (but not COX-1); hepatocyte growth factor (HGF) and its receptor, c-Met; and activation of extracellular signal-regulated kinase 2 (ERK2). Treatment with celecoxib significantly delayed esophageal ulcer healing and suppressed ulceration-triggered increases in esophageal epithelial cell proliferation, c-Met mRNA and protein expression, and ERK2 activity. In an ex vivo organ-culture system, exogenous HGF significantly increased ERK2 phosphorylation levels in esophageal mucosa. A structural analog of celecoxib, SC-236, completely prevented this effect. These findings indicate that celecoxib delays esophageal ulcer healing by reducing ulceration-induced esophageal epithelial cell proliferation. These actions are associated with, and likely mediated by, down-regulation of the HGF/c-Met-ERK2 signaling pathway.

This article has been cited by other articles:

				J. Chai, M. Norng, A. S Tarnawski, and J. Chow A critical role of serum response factor in myofibroblast differentiation during experimental oesophageal ulcer healing in rats Gut, May 1, 2007; 56(5): 621 - 630. [Abstract] [Full Text] [PDF]

				T Hayakawa, Y Fujiwara, M Hamaguchi, T Sugawa, M Okuyama, E Sasaki, T Watanabe, K Tominaga, N Oshitani, K Higuchi, et al. Roles of cyclooxygenase 2 and microsomal prostaglandin E synthase 1 in rat acid reflux oesophagitis Gut, April 1, 2006; 55(4): 450 - 456. [Abstract] [Full Text] [PDF]

				S. Miura, A. Tatsuguchi, K. Wada, H. Takeyama, Y. Shinji, T. Hiratsuka, S. Futagami, K. Miyake, K. Gudis, Y. Mizokami, et al. Cyclooxygenase-2-regulated vascular endothelial growth factor release in gastric fibroblasts Am J Physiol Gastrointest Liver Physiol, August 1, 2004; 287(2): G444 - G451. [Abstract] [Full Text] [PDF]

				B. A. Bondesen, S. T. Mills, K. M. Kegley, and G. K. Pavlath The COX-2 pathway is essential during early stages of skeletal muscle regeneration Am J Physiol Cell Physiol, August 1, 2004; 287(2): C475 - C483. [Abstract] [Full Text] [PDF]

				T. D. WARNER and J. A. MITCHELL Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic FASEB J, May 1, 2004; 18(7): 790 - 804. [Abstract] [Full Text] [PDF]

				D. Wei, L. Wang, Y. He, H. Q. Xiong, J. L. Abbruzzese, and K. Xie Celecoxib Inhibits Vascular Endothelial Growth Factor Expression in and Reduces Angiogenesis and Metastasis of Human Pancreatic Cancer via Suppression of Sp1 Transcription Factor Activity Cancer Res., March 15, 2004; 64(6): 2030 - 2038. [Abstract] [Full Text] [PDF]

				T. Tanigawa, T. Watanabe, M. Hamaguchi, E. Sasaki, K. Tominaga, Y. Fujiwara, N. Oshitani, T. Matsumoto, K. Higuchi, and T. Arakawa Anti-inflammatory effect of two isoforms of COX in H. pylori-induced gastritis in mice: possible involvement of PGE2 Am J Physiol Gastrointest Liver Physiol, January 1, 2004; 286(1): G148 - G156. [Abstract] [Full Text] [PDF]

				R. Caputo, C. Tuccillo, B. A. Manzo, R. Zarrilli, G. Tortora, C. D. V. Blanco, V. Ricci, F. Ciardiello, and M. Romano Helicobacter pylori VacA Toxin Up-Regulates Vascular Endothelial Growth Factor Expression in MKN 28 Gastric Cells through an Epidermal Growth Factor Receptor-, Cyclooxygenase-2-dependent Mechanism Clin. Cancer Res., June 1, 2003; 9(6): 2015 - 2021. [Abstract] [Full Text] [PDF]

				N. A. Callejas, A. Fernandez-Martinez, A. Castrillo, L. Bosca, and P. Martin-Sanz Selective Inhibitors of Cyclooxygenase-2 Delay the Activation of Nuclear Factor kappa B and Attenuate the Expression of Inflammatory Genes in Murine Macrophages Treated with Lipopolysaccharide Mol. Pharmacol., March 1, 2003; 63(3): 671 - 677. [Abstract] [Full Text] [PDF]

				D. Baatar, M. K. Jones, K. Tsugawa, R. Pai, W. S. Moon, G. Y. Koh, I. Kim, S. Kitano, and A. S. Tarnawski Esophageal Ulceration Triggers Expression of Hypoxia-Inducible Factor-1{alpha} and Activates Vascular Endothelial Growth Factor Gene : Implications for Angiogenesis and Ulcer Healing Am. J. Pathol., October 1, 2002; 161(4): 1449 - 1457. [Abstract] [Full Text] [PDF]