Water Extracts of <i>Helicobacter pylori</i> Delay Healing of Chronic Gastric Ulcers in Rats: Role of Cytokines and Gastrin-Somatostatin Link

Abstract

Background: Helicobacter pylori (Hp) is considered as a major risk factor of peptic ulcer, but the pathogenic mechanism of its action has not been fully explained. Aims: This study was designed: (1) to compare the ulcer healing effects of water extract (WE) obtained from type-I cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) expressing Hp and from type-II CagA- and VacA-negative Hp strain with those of vehicle (saline), and (2) to determine the alterations in gastric secretion, gastric blood flow (GBF) and expression of Hp-related cytokines during the ulcer healing in rats treated with toxigenic (type-I) and non-toxigenic (type-II) Hp-derived WE. Methods: Gastric ulcers were produced by serosal application of acetic acid 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 measured by the H₂-gas clearance technique in the ulcer area and non-ulcerated mucosa. Venous blood was withdrawn for the measurement of plasma cytokine (IL-1β and TNFα) levels and plasma and gastric contents were also collected for gastrin and somatostatin determination by specific radioimmunoassay. Results: Gastric ulcers healed gradually in vehicle-treated controls and the ulcer area on days 3, 9 and 15 was reduced by 12, 43 and 92%, respectively. In rats treated with WE of type-I Hp, ulcer healing was significantly delayed, and gastritis and infiltration of ulcerated gastric mucosa with inflammatory cells were observed histologically. The prolongation of ulcer healing by WE of both Hp strains was accompanied by a marked fall in the GBF at the ulcer margin and transient hyposecretion especially in rats given WE of type-I Hp strain. On day 15 of ulcer healing, the plasma concentration of IL-1β and TNFα was negligible in vehicle control rats, but it was significantly elevated particularly in rats treated with WE of type-I Hp. RT-PCR analysis revealed that mucosal expression of IL-1β and TNFα mRNA was significantly upregulated in the gastric mucosa of rats treated with either toxigenic or non-toxigenic Hp WE. The plasma gastrin level 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 ulcer 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.

Enhanced Resistance of Gastric Mucosa to Damaging Agents in the Rat Stomach Adapted to <i>Helicobacter pylori</i> Lipopolysaccharide

“…Moreover, HP LPS exhibits a reduced endotoxic potency in terms of pyrogenicity, lethality, toxicity, mitogenicity and cytokine release [4, 29]. In general, bacterial-derived LPS induce the expression of COX-2 as well as of proinflammatory cytokines, which by themselves are potent inducers of COX-2 expression [6, 7, 8, 30, 31, 32]. Additionally, it has been demonstrated that bacterial endotoxin stimulates the generation of iNOS, with subsequent release of NO and activation of COX-2 [10, 12, 30].…”

Helicobacter pylori and gut hormones

“…A similar depletion of luminal SST release has been demonstrated in male Wistar rats treated with water extract obtained from type I H. pylori. 43 Cats with acquired natural H. pylori infection (cag A Ϫ , pic B Ϫ ) demonstrated fasting plasma gastrin concentrations and pentagastrin-simulated acid secretion levels that were similar to those in uninfected cats. The amount of SST and the number of immunoreactive SST cells in antral tissue were lower in uninfected than in H. pylori-infected cats, 44 in contrast to other reports.…”

An Overview of Acetic Acid Ulcer Models<br>&mdash;The History and State of the Art of Peptic Ulcer Research&mdash;

“…The fact that antibiotics and acid pump inhibitors prevented delayed healing resulting from H. pylori have offered valuable insights into the mechanisms of ulcer healing. Konturek's group 68,69) reported that Cag A and Vac A positive H. pylori water extract could delay ulcer healing in mice and rats. They contend that the underlying mechanism involves reduction of gastric mucosal blood flow, over-expression of cytokines, such as IL-1b and TNFa, and disruption of the balance between serum gastrin/somatostatin.…”