A2BR facilitates the pathogenesis of H. pylori-associated GU by inducing oxidative stress through p38 MAPK phosphorylation

Abstract

Gastric ulcers significantly impact the quality of life of patients, the pathogenesis of which is closely associated with Helicobacter pylori (HP) infection. Oxidative stress is involved in the pathological mechanism of gastric ulcers. Recently, adenosine A2B Receptor (A2BR) was reported to activate the p38MAPK pathway. However, the role of A2BR in gastric ulcers remains unknown. In the present study, the biological function of A2BR in HP-induced gastric ulcers was investigated to explore novel targets for gastric ulcers. GES-1 cells were infected with HP, followed by incubation with 10 μM BAY60-6583 (A2BR agonist) and 25 nM PSB1115 (A2BR antagonist). In HP-infected GES-1 cells, an increased apoptotic rate, enhanced migration ability, excessive release of reactive oxygen species (ROS), increased malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity were observed, accompanied by the activation of p38MAPK signaling, which were dramatically aggravated by BAY60-6583 and alleviated by PSB1115. In animal experiments, rats were treated with 2 mg/kg BAY60-6583 and 10 mg/kg PSB1115, followed by gastric ulcer modeling 30 min later. In HP-infected rats, increased ulcer area, elevated pepsin activity, increased hematoxylin and eosin (HE) pathological scores, increased MDA levels, and decreased SOD activity were observed, which were further aggravated by BAY60-6583 and ameliorated by PSB1115. Finally, the effects of A2BR activation on apoptosis, migration, oxidative stress, and p38MAPK signaling in HP-infected GES-1 cells were reversed by an inhibitor of the p38MAPK pathway. Collectively, A2BR facilitated the pathogenesis of HP-induced gastric ulcers by inducing oxidative stress through p38MAPK activation.