title: 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.
abstract: 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.
authors.affiliation: Department of Veterans Affairs Medical Center, Long Beach, California 90822, USA.
authors.forename: Dolgor
authors.initials: D
authors.lastname: Baatar
authors.forename: Michael K
authors.initials: MK
authors.lastname: Jones
authors.forename: Rama
authors.initials: R
authors.lastname: Pai
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kawanaka
authors.forename: Imre L
authors.initials: IL
authors.lastname: Szabo
authors.forename: Woo S
authors.initials: WS
authors.lastname: Moon
authors.forename: Seigo
authors.initials: S
authors.lastname: Kitano
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Tarnawski
mesh_terms: D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004935:Esophageal Diseases / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014456:Ulcer / Q000378:metabolism* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019859:Proto-Oncogene Proteins c-met; D019950:Mitogen-Activated Protein Kinase 1; D000068579:Celecoxib