Epidermal growth factor and prostaglandin E-2 accelerate mucosal recovery from stress-induced gastric lesions via inhibition of apoptosis

The repair of damaged gastric mucosa is a complex process involving prostag landins (PG) and mucosal growth factors such as epidermal growth factor (EG F). Recently, we postulated that the increased occurence of apoptosis in th e gastric epithelium might be of pathophysiological importance in the devel opment of stress lesions. The aim of the present study was to assess the ef fect of the pretreatment of rats, exposed to 3.5 h of water immersion and r estraint stress (WRS), with EGF and PG (16,16 dmPGE(2)) on the number of st ress lesions, recovery of gastric mucosa from stress and the expression of apoptosis related genes such as caspase-3 and antiapoptotic bcl-2. Rats wer e divided in following groups: (1) vehicle; (2) EGF 100 mug/kg i.p.; (3) 16 ,16 dm-PGE(2) (5 mug/kg i.g.) and caspase-1 inhibitor (ICE-I; 100 mug/kg i. p.). One hour later, the rats were exposed to 3.5 h of WRS and then sacrifi ced immediately (0 h) or at 6, 12, or 24 It after WRS. The number of acute gastric lesions was determined. Gastric epithelial apoptosis was assessed b y TUNEL staining. In addition, mRNA expression of caspase-3, Bcl-2 and proi nflammatory cytokines (IL-1 beta, TNF alpha) was assessed by RT-PCR. PGE(2) generation in gastric mucosa and luminal EGF were determined by RIA. Expos ure to WRS resulted in the development of multiple acute stress erosions (s imilar to 18) which almost completely heated during 24 h. The gastric blood flow was significantly reduced (similar to 70% of intact mucosa) immediate ly after WRS. The expression of mRNA for IL-1 beta and TNF alpha reached th eir peak at 12 h after stress exposure. The apoptosis rate was highest at 6 It after WRS and was accompanied by the highest caspase-3 expression. In r ats pretreated with EGF or 16,16 dm-PGE(2), a significant decrease in caspa se-3 mRNA and upregulation of bcl-2 mRNA as observed as compared to vehicle controls. Caspase-1 inhibitor significantly reduced the number of stress l esions. We conclude that EGF and PGE(2) accelerate healing of stress-induce d lesions due to the attenuation of apoptosis via upregulation of bcl-2 in gastric mucosa. Inhibitors of apoptosis accelerate healing of stress lesion s and may be potentially effective agents in the healing of damaged gastric mucosa. (C) 2001 Elsevier Science Ltd. All rights reserved.