884 The Role of the Ferric Uptake Regulator (Fur) in Helicobacter pylori Resistance to Metronidazole

Abstract

G A A b st ra ct s induced gastric lesions at 6, 12 and 24 h upon 3.5 h of WRS exposure (series B). In separate series, rats with chronic gastric ulcers induced by serosal application of acetic acid (ulcer area=28 mm2) were treated daily for 9 and 15 days with: 1) vehicle (saline); 2) Hp2-20 (0.5 25 mg/kg i.g.) or 3) control peptide Hp1 (10 mg/kg i.g.) with or without non-selective and selective inhibitors of cNOS and iNOS, L-NNA (20 mg/kg-d i.p.) and L-Nil (5 mg/kgd i.p.) without or with the combination with L-arginine (200 mg/kg-d s.c.). The gastric juice was collected for acid output assessment and the number and area of WRS lesions and ulcers were determined planimetrically, the gastric blood flow (GBF) was determined by H2-gas clearance technique and luminal NOx concentration, plasma VEGF levels, the expression of mRNAs for VEGF and FPR mRNA and protein were assessed by ELISA, RTPCR and Western Blot. Hp2-20 dose-dependently inhibited the gastric acid secretion and decreased the number of WRS-induced gastric lesions at 6h, 12 h and 24 h by 16%, 38% and 46%, respectively. Hp2-20 reduced the area of acetic acid ulcers; the dose inhibiting by 50% (ID50) of ulcer area at day 9 upon ulcer induction being 10 mg/kg and this was accompanied by the rise in GBF at ulcer margin, luminal NOx levels and VEGF concentration. Treatment with L-NNA and L-Nil which by themselves increased the area of gastric ulcer significantly reduced the healing effects of Hp2-20 and accompanying rise in the GBF and plasma NOx concentration. These increase in the area of gastric ulcers and accompanying fall in GBF and NOx content induced by L-NNA and L-Nil were reversed by L-arginine added to NOS inhibitors. Upregulation of mRNA and protein for VEGF and FPR at ulcer marginwas observed inHp2-20-treated animals and these effects were significantly attenuated by L-NNA or L-Nil. We conclude that Hp2-20 enhances the mucosal recovery from WRSinduced lesions and accelerates the healing of preexisting gastric ulcers due to upregulation of FRP receptors via mechanism involving inhibition of gastric acid secretion, an activation of NO/NOS pathway and an overexpression and release of VEGF at the ulcer margin responsible for new microvessels formation.