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Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice

¹Department of Clinical Research, University of Berne, Switzerland; ²Department of Neuroanatomy and Molecular Brain Research, Ruhr-University of Bochum, D-44801 Bochum; ³Department of Experimental Clinical Medicine, Ruhr-University of Bochum, D-44780, Germany; ⁴Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland; and ⁵Institute of Pathology, Kantonsspital Lucerne, CH-6000 Lucerne, Switzerland

Submitted 6 September 2005 ; accepted in final form 14 December 2005

Traditional NSAIDs, selective cyclooxygenase (COX)-2 inhibitors, and inhibitors of nitric oxide synthase (NOS) impair the healing of preexisting gastric ulcers. However, the role of COX-1 (with or without impairment of COX-2) and the interaction between COX and NOS isoforms during healing are less clear. Thus we investigated healing and regulation of COX and NOS isoforms during ulcer healing in COX-1 and COX-2 deficiency and inhibition mouse models. In this study, female wild-type COX-1^–/– and COX-2^–/– mice with gastric ulcers induced by cryoprobe were treated intragastrically with vehicle, selective COX-1 (SC-560), COX-2 (celecoxib, rofecoxib, and valdedoxib), and unselective COX (piroxicam) inhibitors. Ulcer healing parameters, mRNA expression, and activity of COX and NOS were quantified. Gene disruption or inhibition of COX-1 did not impair ulcer healing. In contrast, COX-2 gene disruption and COX-2 inhibitors moderately impaired wound healing. More severe healing impairment was found in dual (SC-560 + rofecoxib) and unselective (piroxicam) COX inhibition and combined COX impairment (in COX-1^–/– mice with COX-2 inhibition and COX-2^–/– mice with COX-1 inhibition). In the ulcerated repair tissue, COX-2 mRNA in COX-1^–/– mice, COX-1 mRNA in COX-2^–/– mice, and, remarkably, NOS-2 and NOS-3 mRNA in COX-impaired mice were more upregulated than in wild-type mice. This study demonstrates that COX-2 is a key mediator in gastric wound healing. In contrast, COX-1 has no significant role in healing when COX-2 is unimpaired but becomes important when COX-2 is impaired. As counterregulatory mechanisms, mRNA of COX and NOS isoforms were increased during healing in COX-impaired mice.

wound repair; cyclooxygenase inhibitors; quantitative reverse transcriptase polymerase chain reaction; prostaglandins

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