Acute Gastric Injury Research Articles

Gastric mucosal damage in the course of acute liver failure: which pharmacological options?

Abstract The aim of the present study was to gain further insights into the pathophysiological mechanisms of acute gastric injury during the course of acute hepatic failure (AHF), with a particular view to the search for a therapeutic approach. D-galactosamine HCl (Ga-HCl)-induced AHF model was reproduced in male albino rabbits. Four groups of rabbits were considered: (1) Ga-HCl; (2) Ga-HCl plus 15 μg/kg misoprostol q.i.d. perorally; (3) Ga-HCl plus a 24-h i.v. infusion of 1 mg/kg/h ranitidine; (4) Ga-HCl plus a 24-h i.v. infusion of 0.4 mg/kg/h omeprazole. All rabbits developed a full-blown AHF, irrespective of the treatment. Group 1 rabbits had an overall 84% incidence of hemorrhagic lesions, the gastric body and fundus being most affected, whereas in groups 2, 3 and 4 the incidence was around 25%. Gastric pH greatly decreased in group 1 and 2 but not in group 3 and 4. Group A showed a marked drop in gastric mucosal blood flow and hemoglobin oxygen saturation together with a decreased mucosal hexosamine content associated with an enhanced glucosaminidase activity. These phenomena were prevented by misoprostol and omeprazole but not by ranitidine. Only misoprostol prevented the decrease of gastric mucosal PGE 2 content observed in AHF. These data suggest that during the course of AHF, drugs affecting the cytoprotective mechanisms besides gastric acid secretion per se are the most suitable therapeutic options to counteract the underlying abnormalities taking place in this condition.

Influence of blood microcirculation on the acute NSAID-induced gastric injury: [formula omitted], M.A. Rodríguez∗, J.R. Aracama∗, C. del Pino∗, M.J. Martín∗∗, V. Motilva∗∗, C. Alarcón∗∗, D. Delgado∗∗, J.M. Herrerías∗∗, ∗Servicio Central de Investigación en Ciencias de la Salud de la Universidad de Cádiz. España. ∗∗Servicio de Aparato Digestivo. Hospital Virgen de Macarena. Universidad de Sevilla, España

Influence of blood microcirculation on the acute NSAID-induced gastric injury: [formula omitted], M.A. Rodríguez∗, J.R. Aracama∗, C. del Pino∗, M.J. Martín∗∗, V. Motilva∗∗, C. Alarcón∗∗, D. Delgado∗∗, J.M. Herrerías∗∗, ∗Servicio Central de Investigación en Ciencias de la Salud de la Universidad de Cádiz. España. ∗∗Servicio de Aparato Digestivo. Hospital Virgen de Macarena. Universidad de Sevilla, España

Detection of cytokine transcripts in rat gastric mucosa after exposure to stress using the reverse transcriptase polymerase chain reaction

Detection of cytoklne transcripts in rat gastric mucosa after exposure to stress using the reverse transcrlptase polymerase chain reaction. H. Ernst*, P. Konturek*, A. Ihlm, T. Brzozowski, E.G. Hahn* and S.J. Konturek. *Dept. of Med. I, Univ. Erlangen-Nuremberg, FRG and Inst. of. Physiol., Univ. Sch. Med., Krakow, Poland. Cytokines may contribute to the pathogenesis of stress ulcerations. They may be directly cytotoxic to epthelial cells, or may change the balance towards ulcer formation. Here we investigate the expression of several cytokine transcnpts after a single exposure to stress. Material and Methods: 25 rats were exposed to water restraint stress for 3.5h and then sacri!iced at O, 2, 4, 6 and 12h. The number of stress lesions were counted. Specimens were frozen in liquid nitrogen and total RNA was isolated. cDNA for RT-PCR was synthesized from RNA by reverse transcription using oligo(dT)priming. GAPDH, r~-actin, IL-la, IL-2, IL-6,1FN-¥, TNF-~ and TGFf51 transcripts were analysed by RT-PCR using specific primers. Results: The average number of ulcerations at Oh was 15±3 and then gradually declined to 4 ± 2 at 12h after stress. Controls for r~-actin and GAPDH showed equal expression of transcripts, except that GAPDH transcripts were not detectable 2 h after stress induction. No IL-2, TNF-ct, or IFN-y transcripts were detectable. IL-6 was found in the control group and was also detectable 4 and 6 h after exposure to stress and decreased to below normal levels at 12h. A week signal for ILla was detectable at 4 h after exposure to stress. In contrast, TGFf31 transcripts decreased at 0 and 2 h after stress and its levels did not differ from those of controls at 4, 6, and 1 2 h after exposure to stress. Conclusions: There is expression of a time-dependent pattern of cytokine gentranscripts after exposure to stress. This signaling of cytokines may reflect the normal biological response to stress. INFLUENCE OF BLOOD MICROCIRCULATION ON THE ACUTE NSAID-INDUCED GASTRIC INJURY. J. Esteban*. M.A. Rodriguez*, LR. Aracama*, C. del Pine*, M.J. Martin**, V. Motilva**, C. Alarc6n**, D. Delgado**, J.M. Herrerlas**. *Servicio Central de Investigaci6n en Ciencias de la Salud de la Universidad de Cfidiz. Espaha. **Servieio de Aparato Digestive. Hospital Virgen de Macarena. Universidad de Seville. Espafia.

NSAID-induced acute gastric injury in rats; where are the neutrophils? A histologic study: [formula omitted], A. Erickson, B. Smith. Miami Valley Laboratories, The Protecter & Gamble Company, Cincinnati, Ohio

NSAID-induced acute gastric injury in rats; where are the neutrophils? A histologic study: [formula omitted], A. Erickson, B. Smith. Miami Valley Laboratories, The Protecter & Gamble Company, Cincinnati, Ohio

ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury

In this study we characterized the effects of a novel anti-inflammatory drug, ML 3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7- phenyl-2,3-dihydro-1 H-pyrrolizine-5-yl]-acetic acid), on the gastric mucosa and attempted to determine the mechanism responsible for its apparent stomach-sparing properties. Acute gastric damaging properties of ML 3000 versus indomethacin were examined in the rat, while chronic-type gastric ulcer was examined in the rabbit. At doses of up to 100 mg/kg p.o., ML 3000 did not produce significant acute gastric injury, while indomethacin at 5–20 mg/kg p.o. caused mucosal necrosis and bleeding. ML 3000 significantly inhibited gastric and blood prostaglandin E 2 synthesis, with the higher doses tested (30 and 100 mg/kg) producing comparable effects to that seen with indomethacin at 10 or 20 mg/kg. Gastric and blood leukotriene B 4 synthesis were not significantly affected by either drug. While indomethacin caused a significant increase in leukocyte adherence to mesenteric venules, ML 3000 did not. When administered repeatedly to rabbits, diclofenac caused penetrating ulcer formation in the gastric antrum of the majority of the animals. ML 3000 did not produce any detectable damage at doses of 10 or 30 mg/kg, but an ulcer was observed in one of five rabbits given the 100 mg/kg dose. Prior administration of ML 3000 (10–100 mg/kg) did not significantly affect the extent of gastric damage induced by subsequent oral administration of ethanol. These studies demonstrate that ML 3000 spares the gastric mucosa despite significantly suppressing gastric prostaglandin synthesis. The mechanism underlying the gastric sparing effects of ML 3000 is not completely clear. Suppression of leukotriene synthesis was seen in some, but not all experimental models and non-specific gastroprotective properties were not observed.

Increased Expression of c-met Messenger RNA Following Acute Gastric Injury in Rats

The aim of the present study was to evaluate messenger RNA expression of c-met, a hepatocyte growth factor receptor gene, after gastric mucosal injury in rats. Male Sprague-Dawley rats were fasted for 24 hours, received 0.6 N hydrochloric acid (HCl), and served for polyadenylated RNA extraction from the oxyntic gastric mucosa. The transcripts of rat c-met gene were analyzed by reverse-transcript polymerase chain reaction and Northern blotting. Although it was detected even before the HCl administration, the c-met expression increased 6, 24 and 48 hours after the HCl administration. Thereafter, gastric mucosal injury diminished and the c-met expression declined. Hepatocyte growth factor reportedly plays an important role in gastric cell proliferation. The increased c-met expression indicates that this gene may participate in the healing process of gastric mucosa after injury.

Increased production of transforming growth factor α following acute gastric injury

Transforming growth factor a (TGF-α) production recently has been found in normal mammalian gastric mucosa. Inasmuch as TGF-α and epidermal growth factor (EGF) both stimulate epithelial cell migration and proliferation and suppress gastric acid secretion, the authors of the current study proposed that these growth factors may participate in tissue repair after acute gastric mucosal injury. Consequently, TGF-α and EGF production were examined after orogastric administration of either acidified taurocholate or 0.6 mol/L HCl to rats. TGF-α messenger RNA (mRNA) expression increased in a dose- and time-dependent manner after administration of taurocholate, whereas EGF mRNA expression was not detected. Radioimmunoassay of gastric mucosal scrapings obtained 6 hours after gastric injury induced by 0.6 mol/L HCl showed a 2.1-fold increase in immunoreactive TGF-α but no increase in immunoreactive EGF. In addition, there was a 68-fold increase in immunoreactive TGF-α in gastric juice within 30 minutes of gastric instillation of HCl and, again, no increase in immunoreactive EGF. There is a rapid appearance of TGF-α in the gastric juice within 30 minutes of injury, which is followed by increased expression of TGF-α mRNA and protein in the gastric mucosa. These studies suggest that locally produced TGF-α may participate in gastric mucosal repair following acute gastric injury to rats.

P-325 - Capsaicin-sensitive sensory neurons in the recovery of acute gastric injury induced by taurocholic acid in the rat

P-325 - Capsaicin-sensitive sensory neurons in the recovery of acute gastric injury induced by taurocholic acid in the rat

Acute gastric mucosal injury induced by toxins from Tityus serrulatus scorpion venom: a novel experimental model in the rat

The effect of a partially purified fraction (T 1) and toxin γ purified from Tityus serrulatus scorpion venom, on gastric mucosa were investigated in anesthetized rats. The animals were injected i.v. with the T 1 fraction (37.5 μg/100g) or with saline and 60 min later were sacrificed and the stomachs resected. The gastric juice was measured and stereoscopic examination of the stomachs made. In animals injected with the T 1 fraction there was an increase in volume, acidity and pepsin output of rat stomach. The T 1 fraction also induced acute gastric injuries in the glandular mucosa, consisting of circular or linear ulcers, and punctiform lesions. Intravenous injection of 20 μg/100 g of a pure toxin obtained from Tityus serrulatus scorpion venom (toxin γ) also induced similar lesions in the rat stomach. Our data indicate that the injection of T 1 fraction or toxin γ are good models to induce acute gastric ulcers in a short period of time in anesthetized rats.

The role of platelet activating actor in acute gastric injury and its protection by sucralfate

Platelet activating factor, a potent inflammatory mediator, has been reported to induce gastrointestinal damage, whereas its inhibition or antagonism is associated with mucosal protection. The aim of the present study was to elucidate the association between acute experimental gastric damage and mucosal platelet activating factor generation in the rat, and to evaluate the protective effect of sucralfate in relation to mucosal platelet activating factor formation. Gastric damage in the rat was induced by either subcutaneous injection of indomethacin 30 mg/kg or intragastric administration of aspirin 100 mg/kg, hydrochloric acid 0.6 N, taurocholate 30 mM, ethanol 96%, or sodium chloride 25%. All agents induced a significant increase in mucosal platelet activating factor levels concomitantly with induction of mucosal damage. Pretreatment with sucralfate 150 mg/rat provided a significant macroscopic and microscopic mucosal protection in all experimental models. This protection was associated with a significant decrease in mucosal platelet activating factor level in the hydrochloric acid, taurocholate, ethanol and hyperosmolar sodium chloride treated rats, whereas it remained unchanged in the aspirin and indomethacin treated rats. The data imply that platelet activating factor may have a limited role in the pathogenesis of indomethacin or aspirin induced damage, where other mechanisms such as cyclooxygenase inhibition dominate. In the damage induced by topical strong irritants, platelet activating factor may have a major pathogenetic role.

Central regulation of gastric acid secretion by paltelet-activating factor in anesthesized rats

PAF has been implicated in the pathogenesis of acute gastric injury. When given peripherally, PAF induces severe gastric mucosal damage. PAF metabolizing enzymes are present in the brain but the central effects of PAF on the stomach are unknown. We have investigated in the rat the gastric secretion and gross mucosal integrity in response to intracerebroventricular (icv) PAF and compared in with that to icv TRH, a known central gastric secretagogue. Gastric acid output was markedly increased by TRH (171.6±26.3 μmol/h mean ± SE) and by 20μg/kg/h iv pentagastrin (107.6±23.6) when compared to controls receiving icv vehicle (20.2±7.5; p<0.01 for both). In contrast, acid output decreased after icv PAF (13.5±7.5). Furthermore, icv PAF markedly inhibited acid output stimulated by iv pentagastrin (45.1±7.03; p<0.05). Morphological studies showed acute gastric mucosal erosions after icv TRH and no damage was observed after icv PAF or vehicle. Thus, icv PAF reduces pentagastrin stimulated acid output and does not alter gastric mucosal integrity, whereas icv TRH stimulates acid secretion and induces gastric injury. The opposite effects of PAF and TRH suggests the existence of a gastric modulatory system at the central level.

Analysis of mast cell function in biological responses not involving IgE.

Mast cells are critical for the expression of certain IgE-mediated responses, but the precise contributions of mast cells to biological processes not involving IgE are obscure. We have employed genetically mast cell-deficient WBB6F1-W/Wv and WCB6F1-S1/S1d mice to investigate the roles of mast cells in several different biological responses. This work strongly suggests that mast cells are not required for the elicitation of contact sensitivity (CS) responses, suppressor T cell-dependent tolerance to CS, reserpine-induced inhibition of CS responses, or bleomycin-induced pulmonary fibrosis. By contrast, mast cells appear to contribute to the acute gastric injury induced by ethanol and the acute inflammation of the skin induced by croton oil.

Role of glutathione in gastric mucosal cytoprotection.

Exogenous thiol compounds have been reported to protect the stomach from ethanol-induced necrotic lesions. The gastric mucosa contains high levels of an endogenous thiol, glutathion (GSH). Because of the known role of glutathione in protecting against hepatic injury, its role in gastric mucosal cytoprotection was of interest. By use of an animal model for acute gastric injury from ethanol, a close parallel relation between depletion of endogenous mucosal GSH and induction of mucosal protection was demonstrated. Surprisingly, mucosal protection varied inversely with the level of mucosal GSH obtained after treatment with specific GSH-depleting agents (diethyl maleate and cyclohexene-1-one). Depletion of gastric mucosal GSH was associated with an increase in the mucosal content of prostaglandins 6-keto F1 alpha and F2 alpha but not E2. The protective effect induced by GSH-depleting agents was partially reversed by indomethacin in some but not all studies. Although GSH depletors increased gastric juice volume, protection with these agents persisted after the volume and mucosal GSH had returned to control levels and also was not reversed by increasing the dose of ethanol threefold to overcome a possible dilutional effect. We conclude that, contrary to apparent predictions, depletion of endogenous gastric GSH protects the stomach from acute ethanol-induced injury. Although the mechanism of this protection is unknown, a mediation by endogenous release of prostaglandins seems to play a minor role since diethyl maleate was protective even in indomethacin-treated animals.