Role of heat shock proteins in gastric mucosal protection.

Heat shock proteins (HSP) are crucial for the maintenance of cellular homeostasis during normal cell growth and for survival during and after various cellular stresses. Gastric surface mucous cells are the first line of defence against insults derived from ingested foods and Helicobacter pylori infection. Primary cultures of gastric surface mucous cells from guinea-pig fundic glands exhibited a typical heat shock response after exposure to elevated temperature or metabolic insults, such as ethanol and hydrogen peroxide, and they were able to acquire resistance to these stressors. Restraint and water immersion stress rapidly activated heat shock factor 1 (HSF1) in rat gastric mucosa within 15 min and induced HSP70 mRNA expression and its protein accumulation. The extent of the induction inversely correlated with the severity of mucosal lesions, suggesting an important role of HSP70 in gastric mucosal defence. This heat shock response appeared to be mediated by the alpha1A-adrenoceptor. The HSP70 family functions as a molecular chaperone and reduces stress-induced denaturation and aggregation of intracellular proteins. In addition to its chaperoning activities, HSP70 has been suggested to exert its cytoprotective action by protecting mitochondria and by interfering with the stress-induced apoptotic programme. Recently, we introduced geranylgeranylacetone as a non-toxic HSP70 inducer. This compound weakly stimulated HSP70 induction in cultured gastric mucosal cells and gastric mucosa by directly activating HSF1 and markedly augmented HSP70 induction in response to subsequent exposure to stress. Thus, non-toxic HSP70 inducers may have a potential benefit for the prevention and treatment of stress ulcer.