Water extracts of Helicobacter pylori delay healing of chronic gastric ulcers in rats: Role of cytokines and gastrin-somatostatin link

Background: Helicobacter pylori (Hp) is considered as a major risk factor o f peptic ulcer, but the pathogenic mechanism of its action has not been ful ly explained. Aims: This study was designed: (1) to compare the ulcer heali ng effects of water extract (WE) obtained from type-I cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) expressing Hp and from typ e-II CagA- and VacA-negative Hp strain with those of vehicle (saline), and (2) to determine the alterations in gastric secretion, gastric brood flow ( GBF) and expression of Hp-related cytokines during the ulcer healing in rat s treated with toxigenic (type-I) and non-toxigenic (type-II) Hp-derived WE . Methods: Gastric ulcers were produced by serosal application of acetic ac id in rats with or without gastric fistula treated with vehicle (saline) or WE originating from type-I or type-II Hp administered intragastrically on days 1, 3, 5 and 7 upon ulcer induction. On days 3, 9 and 15, animals were lightly anesthetized with ether, the abdomen was opened and the GBF was mea sured by the H-2-gas clearance technique in the ulcer area and non-ulcerate d mucosa. Venous blood was withdrawn for the measurement of plasma cytokine (IL-1 beta and TNF alpha) levels and plasma and gastric contents were also collected for gastrin and somatostatin determination by specific radioimmu noassay. Results: Gastric ulcers healed gradually in vehicle-treated contro ls and the ulcer area on days 3, 9 and 15 was reduced by 12, 43 and 92%, re spectively. In rats treated with WE of type-I Hp, ulcer healing was signifi cantly delayed, and gastritis and infiltration of ulcerated gastric mucosa with inflammatory cells were observed histologically. The prolongation of u lcer healing by WE of both Hp strains was accompanied by a marked fall in t he GBF at the ulcer margin and transient hyposecretion especially in rats g iven WE of type-I Hp strain. On day 15 of ulcer healing, the plasma concent ration of IL-1 beta and TNF alpha was negligible in vehicle control rats, b ut it was significantly elevated particularly in rats treated with WE of ty pe-I Hp. RT-PCR analysis revealed that mucosal expression of IL-1 beta and TNF alpha mRNA was significantly upregulated in the gastric mucosa of rats treated with either toxigenic or non-toxigenic Hp WE. The plasma gastrin le vel was significantly higher and the luminal concentration of somatostatin was significantly lower in rats treated with Hp-WE than in vehicle-treated controls and these alterations were more pronounced in rats treated with WE type-I than type-II Hp. Conclusions: WE of toxigenic Hp strain delays ulce r healing due to the reduction in the gastric microcirculation at the ulcer margin, the overexpression of inflammatory cytokines and the impairment of the gastrin-somatostatin link.