Antiangiogenic effect of a highly selective cyclooxygenase-2 inhibitor on gastric ulcer healing in rats.
ABSTRACT Selective cyclooxygenase-2 (COX-2) inhibitors have been shown to produce fewer gastrointestinal adverse reactions when compared with conventional nonselective nonsteroidal anti-inflammatory drugs and they suppress angiogenesis in tumors. The purpose of the present study was to investigate the effects of highly selective COX-2 inhibitor on angiogenesis and protein expression of angiogenic factor during gastric ulcer healing. Gastric ulcers were induced in male Sprague-Dawley rats by a luminal application of acetic acid solution. Rofecoxib, a selective COX-2 inhibitor, was administered at a dose of 10 mg/kg/day by gastric intubation for 14 successive days. The ulcer size was measured at different time intervals after ulcer induction. The microvessels that were immunohistologically positive for von Willebrand factor within the ulcer bed were counted. The protein levels of basic fibroblast growth factor (bFGF) and concentration of prostaglandin E(2) (PGE(2)) in the ulcer tissues were analyzed with Western blotting and immunoassay methods, respectively. The results demonstrated that rofecoxib treatment significantly increased the ulcer size at days 6, 10, and 15. It decreased the number of microvessels, bFGF protein expression, and PGE(2) level in the ulcer base at day 6. The findings that highly selective COX-2 inhibitor delayed ulcer healing in rats and impaired angiogenesis in the ulcer base raise cautions regarding the use of COX-2 inhibitors in patients with gastric ulcers.
SourceAvailable from: John L Wallace
Article: Mucosal Repair and COX2 Inhibition[Show abstract] [Hide abstract]
ABSTRACT: The healing of gastric ulcer is a complicated process that involves the proliferation of epithelial and endothelial cells and the concerted actions of a wide range of growth factors. Prostaglandins play an important role in ulcer healing. Expression of cyclooxygenase-2 (COX-2) is markedly upregulated around the margins of gastric ulcers and its inhibition leads to a delay of ulcer healing. Several of the growth factors that promote ulcer healing may work in part through COX- 2-dependent mechanisms. Angiogenesis, which is crucial to ulcer healing, is tightly regulated by growth factors. Treatment with selective COX-2 inhibitors appears to alter the balance of serum levels of growth factors, favoring an inhibition of angiogenesis. Given the importance of COX-2 in regulating ulcer healing, caution should be taken in the use of selective inhibitors of COX-2 by patients at risk of ulcer disease. Key Word: ulcer healing, angiogenesis, cyclooxygenase, prostaglandin, endothelium, platelets.Current Pharmaceutical Design 10/2003; 9(27):2207-2211. DOI:10.2174/1381612033454027 · 3.29 Impact Factor
Ensho Saisei 01/2004; 24(6):656-660. DOI:10.2492/jsir.24.656
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ABSTRACT: Recent evidence suggests that cyclooxygenase (COX)-2 is a mediator of angiogenesis, and COX-2 activity is known to be upregulated in the rheumatoid arthritis (RA) synovium. We examined whether mediation of angiogenesis by COX-2 was occuring in cells of the RA synovium and in microvascular endothelial cells (ECs) that are similar to those found in the RA synovium. We demonstrate that rofecoxib, a selective COX-2 inhibitor, acts directly on human dermal microvascular ECs (HMVECs) to inhibit their chemotactic and tube forming ability. Likewise, pretreatment of HMVECs with rofecoxib significantly inhibited their ability to form tubes induced by conditioned media (CM) of activated RA synovial fibroblasts. When RA synovial fibroblasts were pretreated with rofecoxib for 16 h and then stimulated with interleukin (IL)-1β, their CM induced significantly less HMVEC tube formation when compared with CM from vehicle-treated RA synovial fibroblasts. ELISAs performed on activated RA fibroblast CM for known proangiogenic factors demonstrated a significant reduction in bFGF, in addition to the expected decrease in PGE2. Our studies suggest that COX-2-induced angiogenic activity is an active mechanism within diseased synovium and may provide an additional rationale for the use of COX-2 inhibitors in RA.Experimental and Molecular Pathology 06/2003; 74(3):282-290. DOI:10.1016/S0014-4800(03)00019-4 · 2.88 Impact Factor