Involvement of cyclooxygenase (COX)-2 products in acceleration of ulcer healing by gastrin and hepatocyte growth factor.

Ulcer healing involves expression of various growth factors including hepatocyte growth factor (HGF) at the ulcer margin and the rise in plasma gastrin but the effects of locally applied HGF and gastrin, which are known to act as trophic factors for the gastric mucosa, with or without neutralizing antibodies against HGF and gastrin or COX-1 and COX-2 inhibitors on ulcer healing and the expression of cyclooxygenase (COX)-1 and COX-2 during this healing have been little studied. Rats with gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2) received a submucosal injection of either: 1)vehicle (saline), 2) HGF and 3) gastrin with or without neutralizing antibodies against HGF and gastrin or treatment with indomethacin (2 mg/kg-d i.p.), a non-specific inhibitor of COX, or NS-398 (5 mg/kg-d i.g.) and Vioxx (10 mg/kg-d i.g.), both highly specific COX-2 inhibitors. Each growth factor and specific antibodies against HGF and gastrin (100 ng/100 microl each) were injected just around the ulcer immediately after ulcer induction and this local application was repeated at day 2 following anesthesia and laparotomy. At day 13 and 21, the area of ulcers was determined by planimetry, the gastric blood flow (GBF) at ulcer margin was examined by H2-gas clearance technique and mucosal generation of PGE2 and the expression of COX-1 and COX-2 mRNA in the non-ulcerated and ulcerated gastric mucosa was analyzed using RT-PCR. The gastric ulcers healed progressively within 21 days and this effect was accompanied by significant increase in the GBF at the ulcer margin and expression of COX-2 mRNA and COX-2 protein at the ulcer area. Treatment with HGF and gastrin significantly accelerated the rate of ulcer healing and raised GBF at ulcer margin causing further significant upregulation of COX-2 mRNA and COX-2 protein (but not of COX-1 mRNA ) in the ulcerated mucosa. The upregulation of COX-2 mRNA induced by HGF was significantly attenuated by the concurrent local treatment with antibody against this growth peptide. Indomethacin and both COX-2 inhibitors significantly prolonged the ulcer healing, while suppressing the generation of PGE2 in non-ulcerated and ulcerated gastric mucosa and the GBF at ulcer margin. The acceleration of ulcer healing by HGF and gastrin and accompanying rise in the GBF at ulcer margin were significantly attenuated by the concurrent treatment with indomethacin or NS-398 and Vioxx. HGF injections produced a significant rise in the plasma gastrin levels and this was significantly attenuated by the cotreatment with NS-398. We conclude that 1) neutralization of HGF and gastrin by their specificantibodies delays ulcer healing due fall in the microcirculation around the ulcer and a decrease in the COX-2 expression, 2) COX-2 derived prostaglandins may play an important role in acceleration of the ulcer healing by various growth factors including HGF and gastrin, 3) enhancement of the local pool for growth factors such as HGF and gastrin at the ulcer site could offer a new modality for treatment of gastric ulcer.