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 prostaglandins (PG) and mucosal growth factors such as epidermal growth factor (EGF). Recently, we postulated that the increased occurrence of apoptosis in the gastric epithelium might be of pathophysiological importance in the development of stress lesions. The aim of the present study was to assess the effect of the pretreatment of rats, exposed to 3.5 h of water immersion and restraint stress (WRS), with EGF and PG (16,16 dmPGE(2)) on the number of stress lesions, recovery of gastric mucosa from stress and the expression of apoptosis related genes such as caspase-3 and antiapoptotic bcl-2. Rats were divided in following groups: (1) vehicle; (2) EGF 100 microg/kg i.p.; (3) 16,16 dm-PGE(2) (5 microg/kg i.g.) and caspase-1 inhibitor (ICE-I; 100 microg/kg i.p.). One hour later, the rats were exposed to 3.5 h of WRS and then sacrificed immediately (0 h) or at 6, 12, or 24 h after WRS. The number of acute gastric lesions was determined. Gastric epithelial apoptosis was assessed by TUNEL staining. In addition, mRNA expression of caspase-3, Bcl-2 and proinflammatory cytokines (IL-1 beta, TNFalpha) was assessed by RT-PCR. PGE(2) generation in gastric mucosa and luminal EGF were determined by RIA. Exposure to WRS resulted in the development of multiple acute stress erosions ( approximately 18) which almost completely healed during 24 h. The gastric blood flow was significantly reduced (approximately 70% of intact mucosa) immediately after WRS. The expression of mRNA for IL-1 beta and TNF alpha reached their peak at 12 h after stress exposure. The apoptosis rate was highest at 6 h after WRS and was accompanied by the highest caspase-3 expression. In rats pretreated with EGF or 16,16 dm-PGE(2), a significant decrease in caspase-3 mRNA and upregulation of bcl-2 mRNA as observed as compared to vehicle controls. Caspase-1 inhibitor significantly reduced the number of stress lesions. We conclude that EGF and PGE(2) accelerate healing of stress-induced lesions due to the attenuation of apoptosis via upregulation of bcl-2 in gastric mucosa. Inhibitors of apoptosis accelerate healing of stress lesions and may be potentially effective agents in the healing of damaged gastric mucosa.
Konturek
P C
PC
First Department of Medicine I, University Erlangen-Nuremberg, Krankenhasustrasse 12, D-91054 Erlangen, Germany. pkonturek@aol.com
Brzozowski
T
T
Duda
A
A
Kwiecien
S
S
Löber
S
S
Dembinski
A
A
Hahn
E G
EG
Konturek
S J
SJ
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D007101:Immersion; D007375:Interleukin-1 / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012039:Regional Blood Flow; D015843:Serpins / Q000494:pharmacology; D013270:Stomach / Q000098:blood supply / Q000473:pathology*; D013276:Stomach Ulcer / Q000209:etiology / Q000503:physiopathology; D013312:Stress, Physiological / Q000150:complications / Q000209:etiology / Q000473:pathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014764:Viral Proteins; D014945:Wound Healing / Q000187:drug effects
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D004815:Epidermal Growth Factor; C074641:interleukin-1beta-converting enzyme inhibitor; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D015232:Dinoprostone; D015064:16,16-Dimethylprostaglandin E2