Angiogenesis, cell proliferation and apoptosis in gastric ulcer healing. Effect of a selective cox-2 inhibitor.
To elucidate the role of cyclooxygenase-2, we compared the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, and ibuprofen, a nonselective cyclooxygenase inhibitor, on the evolution of acetic-acid-induced gastric ulcers in rats, evaluating growth factor expression, the angiogenic process, cell proliferation and cell apoptosis. Levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), angiogenesis and cell proliferation were analysed by immunohistochemical methods, and apoptosis was evaluated by an enzyme immunoassay. Both growth factors and microvessels appeared to be abundant in the granulation tissue of the ulcer bed. Rofecoxib (2.5 mg/kg/day) and ibuprofen (100 mg/kg/day) delayed ulcer healing, but only rofecoxib treatment provoked a reduction of bFGF expression and inhibition of the development of new microvessels. No changes in VEGF expression were detected. Results also showed that proliferation and apoptosis were increased in control ulcerated animals. Rofecoxib reduced significantly both processes. These findings demonstrate that a reduction of bFGF expression and an antiangiogenic action, as well as proliferation/apoptosis inhibition, are some of the mechanisms possibly implicated in the delay in ulcer healing seen after the administration of the highly selective COX-2 inhibitor rofecoxib.
Sánchez-Fidalgo
Susana
S
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Spain.
Martín-Lacave
Inés
I
Illanes
Matilde
M
Motilva
Virginia
V
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D007783:Lactones / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D018809:Proliferating Cell Nuclear Antigen; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; C116926:rofecoxib; D016222:Fibroblast Growth Factor 2; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen