Involvement of ornithine decarboxylase and polyamines in epidermal growth factor-induced recovery of gastric mucosa from gastric lesions provoked by stress.
Polyamines such as spermine or putrescine, resulting from increased activity of ornithine decarboxylase (ODC), are known for gastroprotective and mucosal growth promoting effects but little information is available about their role in the acceleration of the healing of stress-induced gastric lesions by epidermal growth factor (EGF). In this study, rats with intact or suppressed ODC activity by alpha-difluoromethylornithine (DFMO, 400 mg/kg i.p.) were subjected to 3.5 h of water immersion and restraint stress (WRS) without or with intragastric (i.g.) administration of spermine and putrescine or with subcutaneous (s.c.) injection of EGF. At 0, 2, 6, 12 and 24 h after stress, rats were killed and the number of gastric lesions was counted, gastric blood flow (GBF) was recorded by the H2-gas clearance technique, the gene expression of ODC mRNA using reverse-transcriptase polymerase chain reaction (RT-PCR) and the ODC activity in this mucosa were determined in oxyntic mucosa. Stress produced gastric lesions combined with decreased GBF (by approximately 43%), but at 2, 6, 12 and 24 h after stress, these lesions and the fall in GBF were gradually attenuated. Healing of stress lesions was accompanied by strong stimulation of ODC mRNA expression and by an immediate increase in enzyme activity, with a peak occurring about 6 h after stress. Pretreatment with DFMO or salivectomy (which resulted in a marked fall in luminal EGF levels and mucosal DNA synthesis) delayed significantly the healing of stress lesions. EGF or spermine significantly accelerated the ulcer healing and raised the GBF. Suppression of endogenous generation of prostaglandins (PGs) with indomethacin (5 mg/kg i.p.) almost completely reversed the EGF- and spermine-induced acceleration of the healing of stress lesions and the accompanying rise in GBF. DFMO significantly reduced the enhancement in healing and the rise in the GBF induced by EGF, but failed to influence those induced by exogenous spermine. The acceleration of the healing induced by spermine or EGF and accompanying hyperemia were not affected by salivectomy. We conclude that (1) upregulation of the ODC transcript, increased ODC activity and polyamines play an important role in mucosal recovery from stress lesions due to acceleration of mucosal repair and an increase in gastric microcirculation, (2) increased ODC activity and resulting excessive polyamine release appear to act as primary mediators of EGF-induced acceleration of healing of stress lesions and (3) endogenous PGs cooperate with EGF and polyamines in mucosal repair from stress ulcerations.
Institute of Physiology, Jagiellonian University School of Medicine, Cracow, Poland.
T
T
Brzozowski
P C
PC
Konturek
S J
SJ
Konturek
I
I
Brzozowska
S
S
Kwiecien
E G
EG
Hahn
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D011700:Putrescine / Q000494:pharmacology*; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D012469:Salivary Glands / Q000601:surgery; D013096:Spermine / Q000494:pharmacology*; D013276:Stomach Ulcer / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D013315:Stress, Psychological; D014945:Wound Healing / Q000187:drug effects*
D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D013096:Spermine; D004815:Epidermal Growth Factor; D009955:Ornithine Decarboxylase; D011700:Putrescine; D007213:Indomethacin; D000518:Eflornithine