Role of extracellular signal-regulated kinase 1/2 in pathogenesis of stress-induced gastric ulcer / 第二军医大学学报

ABSTRACT

Objective:To investigate the role of extracellular signal-regulated kinase 1/2(ERK1/2)signal pathway in the pathogenesis of stress-induced gastric ulcer.Methods:Animal model of stress-induced gastric ulcer was established in rats with water-immersion restraint(WIR)stress.The mucosal activation of ERK1/2 was observed before and 5,15 and 30 min,and 1, 2 and 3.5 h after WIR stress.Some animals were also treated with an intravenous injection of PD98059(1 mg/kg),a specific ERK1/2 inhibitor,1 h prior to WIR stress.Expression of total ERK1/2 and caspase-3 were detected by Western blot analysis; ERK1/2 activity was measured by kinase activity assay using myelin basic protein as a specific substrate.DNA-binding activities of the transcription factors activator protein-1(AP-1)and nuclear factor-?B(NF-?B)were determined by electrophoretic mobility shift assays(EMSA).Mucosal TNF-?and IL-1?mRNA expression was analyzed by Northern blot analysis.The degrees of the gastric mucosal lesions were expressed as ulcer index(UI)and pathological evaluation.Apoptosis in the gastric mucosa was examined by an in situ TdT-mediated dUTP nick-end labeling(TUNEL)method.Results:Activated ERK1/2 was very weakly expressed in the gastric mucosa of normal rats.ERK1/2 was rapidly activated in the gastric mucosa of rats 15 min after WIR stress and the activity reached the maximal after 3.5 h.Pretreatment with PD98059 significantly inhibited ERK1/2 activation,decreased AP-1 and NF-?B activities and TNF-?and IL-1?mRNA expression,and obviously relieved gastric mucosal lesions,accompanied by caspase-3 activation and increased apoptosis.Conclusion:The present results indicate that ERK1/2 activation plays an important role in the development of stress-induced gastric ulcer.