INVOLVEMENT OF ORNITHINE DECARBOXYLASE AND POLYAMINES IN EPIDERMAL GROWTH FACTOR-INDUCED RECOVERY OF GASTRIC MUCOSE FROM GASTRIC-LESIONS PROVOKED BY STRESS

Polyamines such as spermine or putrescine, resulting from increased ac tivity of ornithine decarboxylase (ODC), are known for gastroprotectiv e and mucosal growth promoting effects but little information is avail able about their role in the acceleration of the healing of stress-ind uced gastric lesions by epidermal growth factor (EGF). In this study, rats with intact or suppressed ODC activity by alpha-difluoromethylorn ithine (DFMO, 400 mg/kg i.p.) were subjected to 3.5 h of water immersi on and restraint stress (WRS) without or with intragastric (i.g.) admi nistration of spermine and putrescine or with subcutaneous (s.c.) inje ction of EGF. At 0, 2, 6, 12 and 24 h after stress, rats were killed a nd the number of gastric lesions was counted, gastric blood flow (GBF) was recorded by the H-2-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 mu cosa. Stress produced gastric lesions combined with decreased GBF(by s imilar to 43%), but at 2, 6, 12 and 24 h after stress, these lesions a nd the fall in GBF were gradually attenuated. Healing of stress lesion s 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 resulte d in a marked fall in luminal EGF levels and mucosal DNA synthesis) de layed significantly the healing of stress lesions. EGF or spermine sig nificantly accelerated the ulcer healing and raised the GBF. Suppressi on of endogenous generation of prostaglandins (PGs) with indomethacin (5 mg/kg i.p.) almost completely reversed the EGF- and spermine induce d acceleration of the healing of stress lesions and the accompanying r ise in GBF. DFMO significantly reduced the enhancement in healing and the rise in the GBF induced by EGF, but failed to influence those indu ced by exogenous spermine. The acceleration of the healing induced by spermine or EGF and accompanying hyperemia were not affected by salive ctomy. We conclude that (1) upregulation of the ODC transcript, increa sed ODC activity and polyamines play an important role in mucosal reco very from stress lesions due to acceleration of mucosal repair and an increase in gastric microcirculation, (2) increased ODC activity and r esulting excessive polyamine release appear to act as primary mediator s of EGF-induced acceleration of healing of stress lesions and (3) end ogenous PGs cooperate with EGF and polyamines in mucosal repair from s tress ulcerations. (C) 1998 Elsevier Science B.V.