T. Brzozowski

Activation of Genes for Superoxide Dismutase, Interleukin-1ß, Tumor Necrosis Factor-a, and Intercellular Adhesion Molecule-1 during Healing of Ischemia-Reperfusion-Induced Gastric Injury

Background: Ischemia followed by reperfusion (I/R) induces gastric lesions, probably due to excessive formation of free radicals, but the role of the scavenger of these radicals, proinflammatory cytokines such as interleukin-1b (IL-1b) and tumor necrosis factora (TNF-a), in the healing of these lesions has not been extensively studied. It is also unknown whether expression of intercellular adhesion molecule-1 (ICAM1), which mediates neutrophil-induced injury and neutrophil infiltration, is involved in the recovery from I/ R lesions.Methods: I/R lesions were induced in Wistar rats by applying a small clamp to the celiac artery for 30 min (ischemia phase), followed by the removal of the clamp for 60 min (reperfusion phase). The influence of I/R on gastric secretion was also tested in rats equipped with a gastric fistula (GF) without or with the exposure to a standard period of I/R. Two series of rats (A and B) were used to determine the effects of exogenous and endogenous superoxide dismutase SOD (series A) and allopurinol, a xanthine oxidase inhibitor (series B), on the mucosal recovery from the gastric lesions induced by I/R. The animals were killed immediately after the exposure to I/R (0 h) and at 3 h, 24 h, or 3, 5, or 10 days after this I/R, the area of gastric lesions being measured by planimetry, and the gastric blood flow (GBF) determined by the H2 gas clearance method. Blood was withdrawn for measurement of plasma IL-1 b and TNF-a levels with enzyme-linked immunosorbent assay, and plasma gastrin with radioimmunoassay. Biopsy samples of oxyntic mucosa were taken for the assessment of SOD, IL-1 b, TNF-a, and ICAM-1 mRNAs by reversetranscription polymerase chain reaction and Southern blot. Results: Exposure to I/R resulted in acute gastric erosions, with the maximal increase of the area of these lesions observed 3 h after the end of I/R. This effect was accompanied by a decrease in the GBF, a significant increase in blood free radicals and plasma gastrin increments, and almost complete suppression of gastric secretion. Starting 24 h after I/R, the gastric superficial lesions progressed into deeper ulcers that healed progressively within 10 days, and this was accompanied by gradual restoration of the gastric secretion and the GBF. Treatment with SOD and allopurinol accelerated significantly the healing of I/R erosions, and this effect was accompanied by a significant increase in the GBF and the attenuation of blood free radicals. At 0, 3, and 12 h after I/R a significant decrease in SOD mRNA was observed, whereas expression of TNFa, IL-1b, and ICAM-1 showed a progressive increase starting immediately after I/R, reaching a maximum on day 3. The plasma level of TNF-a and IL-1b started to increase on day 3 and peaked on day 5 after I/R, being still significantly higher at day 10 than that measured in the vehicle-treated control gastric mucosa. On day 10 the gastric ulcers were almost completely healed, and a decrease in the expression for TNFa, IL-1b, and ICAM-1 mRNA and an increase in the expression of SOD mRNA were observed. Conclusions:1) exposure to I/R produces gastric lesions mediated by the excessive formation of free radicals, resulting in suppression of both gastric microcirculation and secretory activity of the stomach; 2) SOD and allopurinol accelerate the healing of I/R lesions, probably due to suppression of oxygen free radicals and improvement of gastric microcirculation; and 3) the upregulation of SOD mRNA, with subsequent increase in the SOD production and local release of IL-1 b and TNF-a, may activate ICAM-1 expression and neutrophil infiltration, which appear to play an important role in the progression of I/R-induced acute gastric erosions into chronic ulcers.BACKGROUND Ischemia followed by reperfusion (I/R) induces gastric lesions, probably due to excessive formation of free radicals, but the role of the scavenger of these radicals, proinflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), in the healing of these lesions has not been extensively studied. It is also unknown whether expression of intercellular adhesion molecule-1 (ICAM-1), which mediates neutrophil-induced injury and neutrophil infiltration, is involved in the recovery from I/R lesions. METHODS I/R lesions were induced in Wistar rats by applying a small clamp to the celiac artery for 30 min (ischemia phase), followed by the removal of the clamp for 60 min (reperfusion phase). The influence of I/R on gastric secretion was also tested in rats equipped with a gastric fistula (GF) without or with the exposure to a standard period of I/R. Two series of rats (A and B) were used to determine the effects of exogenous and endogenous superoxide dismutase SOD (series A) and allopurinol, a xanthine oxidase inhibitor (series B), on the mucosal recovery from the gastric lesions induced by I/R. The animals were killed immediately after the exposure to I/R (0 h) and at 3 h, 24 h, or 3, 5, or 10 days after this I/R, the area of gastric lesions being measured by planimetry, and the gastric blood flow (GBF) determined by the H2 gas clearance method. Blood was withdrawn for measurement of plasma IL-1beta and TNF-alpha levels with enzyme-linked immunosorbent assay, and plasma gastrin with radioimmunoassay. Biopsy samples of oxyntic mucosa were taken for the assessment of SOD, IL-1beta, TNF-alpha, and ICAM-1 mRNAs by reverse-transcription polymerase chain reaction and Southern blot. RESULTS Exposure to I/R resulted in acute gastric erosions, with the maximal increase of the area of these lesions observed 3 h after the end of I/R. This effect was accompanied by a decrease in the GBF, a significant increase in blood free radicals and plasma gastrin increments, and almost complete suppression of gastric secretion. Starting 24 h after I/R, the gastric superficial lesions progressed into deeper ulcers that healed progressively within 10 days, and this was accompanied by gradual restoration of the gastric secretion and the GBF. Treatment with SOD and allopurinol accelerated significantly the healing of I/R erosions, and this effect was accompanied by a significant increase in the GBF and the attenuation of blood free radicals. At 0, 3, and 12 h after I/R a significant decrease in SOD mRNA was observed, whereas expression of TNF-alpha, IL-1beta, and ICAM-1 showed a progressive increase starting immediately after I/R, reaching a maximum on day 3. The plasma level of TNF-alpha and IL-1beta started to increase on day 3 and peaked on day 5 after I/R, being still significantly higher at day 10 than that measured in the vehicle-treated control gastric mucosa. On day 10 the gastric ulcers were almost completely healed, and a decrease in the expression for TNF-alpha, IL-1beta, and ICAM-1 mRNA and an increase in the expression of SOD mRNA were observed. CONCLUSIONS 1) exposure to I/R produces gastric lesions mediated by the excessive formation of free radicals, resulting in suppression of both gastric microcirculation and secretory activity of the stomach; 2) SOD and allopurinol accelerate the healing of I/R lesions, probably due to suppression of oxygen free radicals and improvement of gastric microcirculation; and 3) the upregulation of SOD mRNA, with subsequent increase in the SOD production and local release of IL-1beta and TNF-alpha, may activate ICAM-1 expression and neutrophil infiltration, which appear to play an important role in the progression of I/R-induced acute gastric erosions into chronic ulcers.

Role of Capsaicin-Sensitive Sensory Nerves in Gastroprotection against Acid-Independent and Acid-Dependent Ulcerogens

Treatment with small doses of topical capsaicin protects the gastric mucosa from the damage by strong irritants but functional ablation of sensory nerves by pretreatment with larger dose of parenteral capsaicin augments the formation of gastric lesions via unknown mechanism. This study was designed to determine the role of gastric acid secretion, mucosal blood flow (GBF) and prostaglandins (PG) generation in the gastroprotection induced by small doses of topical or parenteral capsaicin in rats with intact or capsaicin-deactivated sensory nerves. Gastric lesions were produced in rats with intact sensory nerves (series A) or capsaicin-deactivated nerves (series B) using intragastric (i.g.) application of 100% ethanol, acidified aspirin (ASA) or water immersion and restraint stress (WRS). Pretreatment with i.g. capsaicin (0.12-1.0 mg/kg) in rats with intact sensory nerves (series A) reduced dose-dependently the mucosal damage caused by ethanol, ASA or WRS, the dose inhibiting the lesion area by 50% (ID50) being 0.3, 0.5 and 0.7 mg/kg, respectively. This protection was accompanied by a significant rise in gastric mucosal blood flow (GBF). Parenteral application of capsaicin (1.2-10 mg/kg s.c.) that in intact rats dose-dependently increased GBF, also dose-dependently reduced gastric damage induced by ASA or WRS (but not by ethanol), the ID50 being 5 and 3 mg/kg, respectively. The reduction by i.g. capsaicin of ethanol-or WRS-induced mucosal lesions was accompanied by a rise in GBF and this effect was reversed by indomethacin at a dose that suppressed endogenous PG biosynthesis by about 90%, indicating that PG are involved in the protective activities of topical capsaicin. Furthermore, topical and to a lesser extent parenteral capsaicin given to rats with intact or deactivated sensory nerves inhibited gastric acid and pepsin outputs, suggesting that this inhibition could contribute to the capsaicin-induced gastroprotection against acid-dependent mucosal lesions (ASA or WRS). Capsaicin deactivation of sensory nerves aggravated mucosal lesions induced by all three ulcerogens and this effects was accompanied by a marked decrease in GBF. In such capsaicin-deactivated rats, topical capsaicin also reduced ethanol-, ASA- or WRS-induced lesions, while parenteral capsaicin was effective only in the protection against the damage induced by acidified ASA and WRS but not by ethanol. The protection against WRS lesions and accompanying rise in GBF by parenteral capsaicin were also reversed by the pretreatment with indomethacin applied in a dose suppressing the generation of PG. We conclude that capsaicin is capable of protecting gastric mucosa in rats with both intact and capsaicin-deactivated rats and that this protective activity depends, at least in part, upon its hyperemic and antisecretory effects that may be mediated, at least in part, by endogenous release of PG.

Gastroprotective and ulcer healing effects of nitric oxide-releasing non-steroidal anti-inflammatory drugs

BACKGROUND & AIM New class of nitric oxide-releasing non-steroidal anti-inflammatory drugs was shown to inhibit cyclooxygenase and prostaglandin generation without causing mucosal damage but whether these agents are capable of affecting gastric mucosal damage induced by strong irritants and healing of chronic gastric ulcers remains to be studied. In this investigation, effects of nitric oxide-releasing aspirin and nitric oxide-releasing naproxen were compared with those of native agents on gastric lesions provoked by 100% ethanol and on healing of chronic acetic acid ulcers. RESULTS Both, nitric oxide-releasing aspirin and naproxen dose-dependently attenuated ethanol-induced damage and produced a significant rise in gastric blood flow but did not delay healing of gastric ulcers while native aspirin and naproxen had no influence on ethanol-induced gastric damage but significantly prolonged ulcer healing, reduced gastric blood flow and suppressed mucosal generation of prostaglandin E2. The gastroprotective and hyperaemic effects of both nitric oxide-non-steroidal anti-inflammatory drugs were completely abolished by ODQ, an inhibitor of guanylyl cyclase-cGMP system but not influenced by suppression of nitric oxide-synthase with L-NNA. The damaging effects of native acetyl salicylate acid or naproxen were aggravated by acidification of these non-steroidal anti-inflammatory drugs but the exogenous acid added to nitric oxide-acetyl salicylate acid or nitric oxide-naproxen failed to influence their effect. Despite inhibiting of PGE2 generation, both nitric oxide-releasing derivatives and native aspirin and naproxen failed to affect expression of cyclooxygenase-1 mRNA but upregulated the cyclooxygenase-2 mRNA. Concurrent inhibition of cyclooxygenase-2 by selective inhibitor NS-398 which by itself delayed ulcer healing and attenuated the gastric blood flow at ulcer margin, significantly worsened the effects of these nitric oxide-non-steroidal anti-inflammatory drugs and their parent drugs on ulcer healing and the gastric blood flow at the ulcer margin. CONCLUSIONS 1) Coupling of nitric oxide to aspirin or naproxen attenuates ethanol-induced damage, possibly due to an increase in gastric microcirculation mediated by excessive release and action of nitric oxide that probably compensates for PG deficiency induced by non-steroidal anti-inflammatory drugs; and 2) nitric oxide-non-steroidal anti-inflammatory drug, unlike classic non-steroidal anti-inflammatory drugs, does not affect intact gastric mucosa and fails to delay the healing of pre-existing ulcers.

Melatonin or L-tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole.

Abstract:  Melatonin and l‐tryptophan (Trp) are highly gastroprotective in humans, but no study has assessed their impact on healing of chronic gastroduodenal ulcers in humans. Three groups (A, B and C) of 14 idiopathic patients in each treatment group with gastroduodenal chronic ulcers were treated with omeprazole (20 mg twice daily) combined either with placebo (group A), melatonin (group B) or with Trp (group C). The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after initiation of therapy. Plasma melatonin, gastrin, ghrelin and leptin were measured by RIA. On day 7, omeprazole by itself (group A) had not healed any ulcers, but four ulcers were healed with omeprazole plus melatonin and two with omeprazole plus tryptophan. At day 21, all ulcers were healed in patients treated with melatonin or Trp, but only 10–12 ulcers were healed in placebo‐treated patients. After treatment with omeprazole plus melatonin (group B) or Trp (group C), plasma melatonin levels rose several‐fold above initial values. Plasma gastrin level also rose significantly during treatment with omeprazole plus melatonin or Trp, but it was also significantly increased in patients treated with omeprazole plus placebo. Plasma ghrelin levels did not change significantly after treatment with melatonin or Trp, while plasma leptin increased significantly in patients treated with melatonin or Trp but not with placebo. We conclude that melatonin or Trp, when added to omeprazole treatment, accelerates ulcer healing and this likely depends mainly upon the significant increments in plasma melatonin.

Comparison of Cholecystokinin, Pentagastrin, and Duodenal Oleate in Gastroprotection in Rats

BACKGROUND Cholecystokinin (CCK) and gastrin show a potent influence on gastric secretion and motility, but their role in mucosal integrity has been little studied. METHODS In this study the effects of CCK-8, pentagastrin, and duodenal oleate on acute gastric lesions induced by 100% ethanol were studied in rats. RESULTS CCK-8 was about 13 times more potent than pentagastrin in protecting the gastric mucosa against ethanol damage. CCK released by duodenal oleate also protected gastric mucosa against this damage. The protective effects of CCK-8 were almost completely abolished by the blockage of CCK-A receptors with loxiglumide, whereas the protective effect of pentagastrin was completely abolished by L-365,260. The protective effects of CCK, pentagastrin, or duodenal oleate against ethanol injury were accompanied by a marked increase in luminal content of somatostatin, suggesting that this peptide is implicated in this protection. The protective activity of CCK and pentagastrin against ethanol injury was accompanied by a significant increase in gastric blood flow. Inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine methyl ester abolished almost completely both gastric protection and hyperemia induced by CCK and pentagastrin. Addition of L-arginine, but not D-arginine, restored the protective and hyperemic effects of CCK and pentagastrin. Pretreatment with the sulfhydryl blocking agent N-ethylmaleimide also abolished the protective and hyperemic effects of CCK and pentagastrin. The hyperemia, but not the protection, afforded by CCK and pentagastrin was reduced after sensory nerve deactivation with capsaicin. CONCLUSIONS Both exogenous and endogenous CCK and pentagastrin exert protective activity against ethanol damage, and this effect is mediated through separate receptors, NO, and sulfhydryl-sensitive pathway.

Gastroprotective Effect of Histamine and Acid Secretion on Ammonia-Induced Gastric Lesions in Rats

Background: Previous studies have shown that ammonia produced by Helicobacter pylori urease or administrated intragastrically exhibits a toxic effect on the gastric mucosa. In the present study we investigated the influence of histamine and gastric acid secretion on ammonia (NH4OH)-induced gastric lesions. Methods: The gastric mucosa in rats was exposed to NH4OH (1.5 ml of 250 mM solution) under basal conditions, after administration of histamine (1 mg/kg), urea with urease, and ranitidine (40 mg/kg subcutaneously) given alone or in combination. We measured the area of gastric lesions, gastric blood flow (GBF), plasma gastrin concentration, DNA synthesis, gastric acid secretion and gastric luminal concentration of PGE2. Results: Application of NH4OH resulted in the formation of acute gastric lesions. This effect was accompanied by a fall in GBF, a rise in gastric pH, and a reduction in mucosal DNA synthesis. Administration of histamine 30 min prior to NH4OH reduced the area of gastric lesions. This was accompanied by an increase in GBF, DNA synthesis, and prostaglandin E2 (PGE2) production. Ranitidine given prior to NH4OH enhanced gastric mucosa damage, and reduced GBF and DNA synthesis. This effect was accompanied by a reduction in gastric acid secretion. Ranitidine given prior to histamine abolished gastric acid secretion and the protective effect of histamine against NH4OH-induced damage; these effects were accompanied by a decrease in GBF, DNA synthesis, and concentration of PGE2. Pretreatment with 2% urea with urease given prior to NH4OH reduced NH4OH lesions. This effect was associated with an increase in gastric acid secretion, gastric generation of PGE2, GBF, and DNA synthesis. Ranitidine given prior to urea with urease inhibited gastric acid secretion and the gastroprotective effect of urea-urease gastroprotection. Conclusions: Histamine and gastric secretion exhibit a protective effect against ammonia-induced gastric lesions. This effect appears to depend upon the stimulation of gastric acid secretion and PGE2 production, and the improvement of gastric microcirculation.

Gastric Adaptation to Aspirin and Stress Enhances Gastric Mucosal Resistance against the Damage by Strong Irritants

BACKGROUND Gastric mucosal adaptation to injury induced by repeated application of aspirin (ASA) or stress is a well-documented phenomenon, but it is known whether such adaptation affects the mucosal tolerance to other strong irritants. METHODS In this study gastric adaptation was induced by repeated daily administration of acidified ASA for 4 consecutive days (Series A) or by 3.5H of water immersion and restraint stress (WRS) applied every other day for up to 8 days (series B). When the adaptation to ASA or WRS was fully developed, rats of series A and B were challenged with strong irritants such as 100% ethanol, 200 mM acidified taurocholate (TC), or 25% NaCl for 1 h or with WRS for 3.5 h. RESULTS ASA or WRS applied once produced numerous gastric lesions and deep histologic necrosis accompanied by a decrease in gastric blood flow. With repeated application of ASA or stress the mucosal adaptation to ASA and WRS developed; the area of gastric lesions was reduced by 86% and 56%, respectively, and this was accompanied by a marked decrease of superficial and deep necrosis, and increase in gastric blood flow (GBF) and the enhancement of mucosal regeneration. An increase in mucosal and luminal contents of epidermal growth factor (EGF) and in mucosal expression of EGF receptors was also observed in the mucosa adapted to ASA or stress. In rats adapted to ASA or stress and then challenged with 100% ethanol, 200 mm TC, 25% NaCl, stress or ASA, the areas of macroscopic gastric lesions and deep histologic necrosis were remarkable reduced as compared with those in non-adapted vehicle-treated rats. This was also accompanied by a significant decrease in (GBF), a marked increase of mucosal and luminal contents of EGF and expression of its receptors, and enhanced mucosal cell proliferation. CONCLUSIONS Gastric adaptation to ASA or stress enhances mucosal resistance to the injury induced by strong irritants, and this appears to be mediated by mucosal regeneration, probably resulting from increased luminal and mucosal contents of EGF and excessive expression of its receptors.

Nitric oxide-releasing aspirin protects gastric mucosa against ethanol damage in rats with functional ablation of sensory nerves

AbstractObjective and Design: The aim of the present study was to investigate, whether sensory nerves are involved in the gastroprotection induced by NO releasing non-steroidal anti-inflammatory drugs (NO-NSAID). Material: Studies were performed in Wistar rats with intact or inactivated sensory nerves by pretreatment with large dose of capsaicin (125 mg/kg sc). Treatments: Acute gastric lesions were induced by 100% ethanol (100% EtOH). 1 h before exposure to 100% EtOH, rats received vehicle, aspirin (ASA) or NO-releasing aspirin (NO-ASA) in the same dose (50 mg/kg). The animals were killed 1 h after exposure to 100% EtOH. Methods: Determinations were made of gastric mucosal injury, mucosal gastric blood flow, mucosal mRNA expression of glutathione peroxidase (GPx), zinc copper superoxide dismutase (SOD) and heat shock protein (HSP70) by RT-PCR and protein expression for HSP70 by Western blotting. Results: Pretreatment with ASA aggravated the acute gastric injury induced by 100% EtOH, whereas pretreatment with NO-ASA led to a significant reduction in this injury. Administration of 100% EtOH was accompanied by a pronounced upregulation of HSP70, which was reduced by ASA, but enhanced by NO-ASA application. Sensory deactivation with capsaicin enhanced acute ethanol lesions and led to a significant attenuation in HSP70 expression. In contrast to ASA, NO-ASA attenuated gastric mucosal lesions and significantly upregulated HSP70 expression despite blockade of sensory nerves. NO-ASA, but not ASA, caused an upregulation of SOD and GPx mRNA in gastric mucosa with or without sensory denervation. Conclusions: NO-ASA protects gastric mucosa even after blockade of sensory nerves due to the upregulation of HSP70 expression and attenuation of the oxidative injury resulting from strong upregulation of genes for antioxidant enzymes.

Involvement of Orexigenic Peptides in the Mechanism of Gastric Mucosal Integrity and Healing of Chronic Gastric Ulcers

Orexigenic peptides are group of endocrine hormones exerting a pleiotropic influence on many physiological functions including regulation of the feeding behaviour and energy expenditure, release of growth hormone (GH) and inotropic effects on the heart. Some of these peptides such as ghrelin, originally identified in the gastric mucosa, has been involved not only in control of food intake and growth hormone release but also exerts the immunomodulatory and anti-inflammatory properties. This review summarizes the recent attempts to prove the concept that orexigenic peptides such as ghrelin, orexin-A and obestatin besides playing an important role in the mechanism of food intake, exhibit a potent gastroprotective action against the formation of acute gastric mucosal injury induced by various ulcerogens. This protective effect depends upon vagal activity and hyperemia mediated by NOS/NO and COX/PG systems and CGRP released from sensory afferent nerves. In addition, the appetite peptides such as ghrelin and orexin-A are implicated in the mechanism of the healing of preexisting gastric ulcers due to an activation of specific GHS-R1a and OX-R1 receptors and PG/COX system.

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.