Mechanism Of Gastric Mucosal Protection Research Articles

Green carbon dots derived from Atractylodes macrocephala: A potential nanodrug for treating alcoholic gastric ulcer.

Alcoholic gastric ulcer is a common acute gastric injury disease. The drugs currently used in clinical practice not only cannot fundamentally treat gastric injury, but also have serious side effects. There is an urgent demand for the discovery of a mild drug to treat alcoholic gastric ulcers. Herein, the green carbon dots derived from charred Atractylodes macrocephala (CAM-CDs) were acquired and have been proven to be safe and effective in alleviating alcoholic gastric ulcers at an inhibition rate up to 60%. CAM-CDs can markedly attenuate the gastric mucosa damage such as mucosal defect, bleeding and inflammatory cell infiltration by histopathological examination. Serum and tissue inflammatory cytokine measurements, as well as immunohistochemistry results, indicate that its mechanism of gastric mucosal protection may involve the reduction of IL-1β and TNF-α by regulating inflammatory signaling pathway of the NF-κB/NLRP3 axis, as well as elevation of IL-10 levels. CAM-CDs also can reduce oxidative stress markers (MDA), increase PGE2 and mucin secretion (MUC5AC), and it simultaneously exerts slight inhibition of hydrogen potassium ATPase and pepsin activity to protect gastric mucosa, as well as increases the microbial diversity and regulates species composition of gut microbiota in rats with gastric ulcer. Our work provides a new perspective on utilizing carbon-based nanomaterials in the development of new mild drugs.

Role of renin-angiotensin system and metabolites of angiotensin in the mechanism of gastric mucosal protection.

Angiotensin II, the main effector of the renin-angiotensin system (RAS), is generated from the precursor angiotensinogen by the actions of renin, angiotensin-converting enzyme, chymase and various peptidases. RAS is essential in the control of blood pressure and body fluid homeostasis but their involvement in the mechanism of the protection of gastric mucosa has not been extensively studied. On the other hand, angiotensin-(1-7) which acts on the Mas receptor, exhibits a potent vasodilatory activity and attenuates the gastric lesions induced by various ulcerogens. In this review, the mechanism of RAS, the antagonists of angiotensin AT1 and AT2 receptors and angiotensin-(1-7) in formation of gastric damage is discussed with possible translating relevance to treatment modalities in the protection against gastric mucosal injury.

Polaprezinc (Zinc L-Carnosine) Is a Potent Inducer of Anti-oxidative Stress Enzyme, Heme Oxygenase (HO)-1 — a New Mechanism of Gastric Mucosal Protection

Heme oxygenase (HO)-1 is implicated in cytoprotection in various organs. We tested a possibility that polaprezinc (PZ), an anti-ulcer drug, could induce HO-1 in the gastric mucosa. Male 6-week-old Wistar rats were intragastrically administered PZ. Gastric expression of HO-1 was assessed by real time RT-PCR and western blotting, and localization of HO-1 was observed by in situ hybridization and immunohistochemistry. The levels of HO-1 mRNA were increased in a dose-dependent manner. The levels of HO-1 mRNA were increased 4-fold by PZ at the dose of 200 mg/kg at 3 h as compared with control levels. The levels of immunoreactive HO-1 were increased 3-fold at 6 h. Signals for HO-1 mRNA and immunoreactivity were detected strongly in the surface gastric mucosal cells and moderately in the gastric macrophages. Treatment with an HO-1 inhibitor, stannous mesoporphyrin (SnMP) significantly worsened the HCl-induced acute gastric mucosal lesions and increased the apoptosis of mucosal cells. Mucosal lesions were decreased by pretreatment with PZ, while they were increased by co-administration with SnMP. These data indicate for the first time that PZ is an effective inducer of HO-1 in the stomach. PZ-induced HO-1 functions as a part of the mucosal protective effects of PZ.

Leptin-induced cytosolic phospholipase A2 activation in gastric mucosal protection against ethanol cytotoxicity involves epidermal growth factor receptor transactivation

A pluripotent cytokine, leptin, released locally within the mucosal tissue is an important mediator of the processes of gastric mucosal defense and repair. Here, we report that leptin protection of gastric mucosal cells against ethanol cytotoxicity requires epidermal growth factor receptor (EGFR) participation. We show that the protective effect of leptin against ethanol cytotoxicity was associated with the increased EGFR and cPLA(2) phosphorylation, and characterized by a marked increase in arachidonic acid (AA) release and prostaglandin (PGE(2)) generation. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with Src kinase inhibitor, PP2, and EGFR kinase inhibitor, AG1478, as well as ERK inhibitor, PD98059. Moreover, all three agents evoked also the inhibition in leptin-induced upregulation in cPLA(2) activity, AA release, and PGE(2) generation. Furthermore, changes caused by leptin in EGFR phosphorylation and cPLA(2) activation were susceptible to suppression by GM6001, a metalloprotease inhibitor of membrane-anchored EGFR ligand cleavage. These findings disclose an important link between leptin-induced and Src kinase-mediated EGFR transactivation and the activation of cytosolic phospholipase A(2) that leads to up-regulation in PGE2 production, thus providing new insights into the mechanism of gastric mucosal protection by leptin.

The effect of rebamipide on the expression of proinflammatory mediators and apoptosis in human neutrophils by Helicobacter pylori water-soluble surface proteins.

Helicobacter pylori infection elicits persistent neutrophil infiltration in gastric mucosa. The expression of cyclooxygenase (COX)-2 and inhibition of apoptosis in the neutrophils could contribute to the pathogenesis of H. pylori infection. Rebamipide, a mucosal protective and ulcer-healing drug, has been known to inhibit neutrophil activation. To evaluate the effect of rebamipide on the neutrophils activated by H. pylori water-soluble proteins. After neutrophils were stimulated with H. pylori water extract (HPWE) or pre-treated with rebamipide, the expression of COX-2 mRNA and protein was assessed by quantitative RT-PCR and Western blotting, respectively. Prostaglandin (PG) E2 synthesis was determined by radioimmunoassay. Neutrophil apoptosis was evaluated by cytosolic oligonucleosome-bound DNA ELISA and caspase-3 activity was measured by the detection of p-nitroanilide after cleavage from labelled substrate. Stimulation with HPWE up-regulated COX-2 expression and PGE2 secretion, and inhibited neutrophil apoptosis. Rebamipide suppressed PGE2 secretion from neutrophils dose-dependently. Rebamipide, however, did not affect neutrophil apoptosis and caspase-3 activity. Rebamipide effectively suppressed PGE2 secretion from neutrophils activated by H. pylori water-soluble proteins. This is another possible mechanism of gastric mucosal protection by rebamipide.

Gastrin enhances gastric mucosal integrity through cyclooxygenase-2 upregulation in rats.

Gastrin, PGs, and growth factors have important roles in maintaining gastrointestinal mucosal integrity. Cyclooxygenases (COX-1 and COX-2) are the key enzymes involved in PG synthesis. This study aimed to clarify the mechanisms of gastric mucosal protection by gastrin. Fasted rats were administered subcutaneous gastrin 17 with or without gastrin receptor antagonist YM022 pretreatment. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and COX-2 expression were examined using Western blot analysis. Another series of experiments investigated 1) PGE(2) levels in gastric mucosa, 2) the protective action of gastrin against gastric damage by acidified ethanol, 3) the effects of a specific HB-EGF-neutralizing antibody on gastrin-induced COX-2 expression, and 4) the effects of a specific COX-2 inhibitor NS-398 on PGE(2) synthesis and the mucosal protection afforded by gastrin. Gastrin dose-dependently increased HB-EGF, COX-2 expression, and PGE(2) levels and reduced gastric damage. However, pretreatment with YM022 dose-dependently abolished such effects of gastrin. A specific HB-EGF- neutralizing antibody and an EGF receptor inhibitor decreased gastrin-induced COX-2 expression. NS-398 blocked gastrin-induced PGE(2) synthesis and mucosal protection. In conclusion, this study demonstrates that gastrin enhances gastric mucosal integrity through COX-2, which is partially mediated by HB-EGF, and PGE(2) upregulation in rats.

6 OP Effects of selective and non-selective cyclooxygenase-2 inhibitors on mechanisms of gastric mucosal protection

6 OP Effects of selective and non-selective cyclooxygenase-2 inhibitors on mechanisms of gastric mucosal protection

Further study of experimental gastritis in rats: endocrine and neurocrine profile.

We conducted this study to identify the endocrine and neurocrine mechanisms of gastric mucosal protection in rats with experimental atrophic gastritis (erosive atrophic antritis) induced by prolonged exposure to taurocholate. This resulting gastritis was characterized by a significant reduction of parietal cell mass, a decrease in mucosal thickness, decreased numbers of pyloric glands, infiltration by inflammatory cells, and fibrotic proliferation in the gastric mucosa. Mucosal erosions were also prominent. These morphologic and morphometric findings indicate the presence of erosive atrophic gastritis, as previously described. Fasting levels of serum gastrin increased significantly in the rats with gastritis versus controls, whereas the mucosal gastrin levels did not differ significantly from those of controls. Mucosal levels of somatostatin decreased significantly, and vasoactive intestinal peptide (VIP) increased significantly in the pyloric sphincter region. These findings suggest that these peptides and neuropeptides are involved in the induction of this form of gastritis. The peptides may play an important role in the mechanisms of gastric mucosal protection (i.e., gastrin is an aggressive and somatostatin is a defensive factor, and VIP promotes the reflux of bile into the stomach by relaxing the pyloric sphincter).

Protection against alcohol-induced gastric mucosal injury by nitecapone

1. The mechanism of gastric mucosal protection by an antiulcer agent, nitecapone, against injury was investigated in rats with and without indomethacin pretreatment. 2. Animals received intragastrically either a dose of nitecapone or vehicle alone, followed by ethanol given at various intervals up to 5 hr, and their gastric mucosa subjected to histologic and physicochemical assessment. 3. Ethanol caused extensive gastric hemorrhagic lesions which were essentially prevented by nitecapone at doses of 30 mg and higher per kg body weight. The maximal protection was achieved by 1.5 hr which persisted up to 4 hr and was not thwarted by indomethacin. 4. Physicochemical measurements revealed that nitecapone evoked 78% increase in mucus gel dimension, and showed 21% increase in phospholipids, and the content of sulfo- (22%) and sialomucins (72%). This was accompanied by 1.6-fold increase in mucus viscosity, 31% increase in H + retardation capacity and 2.2-fold increase in hydrophobicity. 5. The results suggest that the gastroprotective action of nitecapone occurs through the enhancement of the physicochemical characteristics of mucus layer.

Participation of Phosphoinositides in Gastric Mucosal Protection by Colloidal Bismuth Subcitrate against Ethanol‐Induced Injury

The mechanism of gastric mucosal protection by an antiulcer agent, colloidal bismuth subcitrate (CBS), against ethanol-induced injury was investigated using in vivo and in vitro systems. The experiments in vivo were conducted with groups of rats with and without indomethacin pretreatment, and the animals received either a dose of CBS (100 mg/kg) or a vehicle (saline), followed 30 min later by ethanol. In the in vitro studies, gastric mucosa segments were cultured in the presence of CBS, ethanol, or both. The results of in vivo experiments revealed that in the absence of CBS, ethanol caused extensive gastric hemorrhagic lesions which were significantly reduced following CBS pretreatment and this effect of CBS was not prevented by indomethacin. The data obtained with gastric mucosal culture established that in comparison to the controls, ethanol caused a 27% decrease in mucin synthesis, while mucin synthesis in the presence of CBS increased by 48%. The increase in mucin synthesis evoked by CBS was accompanied by the enhanced metabolism of mucosal phosphoinositides, as reflected by a decrease in PI (15%) and PIP2 (30%), and an increase in IP1 (26%) and IP3 (67%). In contrast, ethanol, which exhibited detrimental effect on mucin synthesis, caused a decrease in PIP (35%), IP2 (47%) and IP3 (38%), and an increase in PIP2 (80%), and IP1 (51%). However, when the mucosal culture was carried out in the presence of both CBS and ethanol, the detrimental changes evoked by ethanol on mucin synthesis were prevented, and the phosphoinositide and inositide phosphate distribution patterns were quite similar to those in the mucosa cultured in the presence of CBS only.(ABSTRACT TRUNCATED AT 250 WORDS)

Possible mechanism of gastric mucosal protection by epidermal growth factor in rats

The mechanism of the protection by human epidermal growth factor (hEGF) against the gastric mucosal lesions induced by acidified ethanol was studied in rats. At different times following the subcutaneous administration of hEGF (30 μg/kg), intragastric acidified ethanol (EtOH : 0.125 M HCl = 50 : 50 v/v%) was administered to induce an experimental gastric mucosal lesion. Mean length of the lesion in the gastric mucosa was used as a lesion index. Extravasation of intraveneously injected Evans blue into the gastric wall and gastric contents was used as an indicator of vascular permeability. Pretreatment with hEGF decreased both the gastric mucosal lesions and the increase of vascular permeability caused by acidified ethanol with similar time profiles relative to pretreatment with hEGF. Maximal protective actions of hEGF occured about 10 to 30 min after the observed peak plasma concentration of hEGF. Indomethacin and N -ethylmaleimide, but not iodoacetamide, blocked the protective action of hEGF, indicating that endogeneous prostaglandins and/or sulfhydryls may participate in the protective action of hEGF. The content of endogeneous nonprotein sulfhydryls in the gastric mucosa decreased markedly after acidified ethanol. However, pretreated hEGF did not restore the sulfhydryl contents. Thus, it seemed that endegeneous prostaglandins, but not sulfhydryls, are the probable mediators for protection against gastric mucosal injury caused by acidified ethanol.

Gastric mucosal protection by new aryl sulfhydryl drugs.

Alkyl sulfhydryl drugs protect against acute gastric hemorrhagic mucosal lesions. We tested the protective effect of cyclic drugs containing oxidized (KT1-32, KT1-39, KT1-94), or reduced (KT1-66, KT1-109, KT1-293, KT1-720, KT1-756) sulfhydryls. The most potent protective agents (KT1-32, KT1-109, KT1-720, KT1-756) were investigated in detail. Drugs were administered intragastrically to fasted rats 30 min before 100% ethanol (1 ml) or acidified aspirin (10 mg/100 g), and mucosal lesions were measured planimetrically 1 hr later. Control rats receiving only ethanol had lesions involving 14.5% of the glandular mucosa. KT1-32, KT1-109, KT1-720, or KT1-756 (10 mg/100 g) reduced lesions to 0.7, 2.7, 1.8, or 0.7% of glandular stomach respectively. Aspirin-induced lesions involved 1.52% of the glandular mucosa and 10 mg/100 g of KT1-32, KT1-109, or KT1-720, or 2 mg/100 g of KT1-756 diminished the damage to 0.13, 0.02, or 0.04, or 0.00%, respectively. Indomethacin interfered with protection against ethanol by KT1-109, while the sulfhydryl alkylator N-ethylmaleimide abolished protection by both KT1-32 and KT1-109. Among the drugs investigated in detail, KT1-756 increased gastric acid output, while KT1-720 and KT1-756 significantly enhanced pepsin secretion. All four compounds studied in detail (ie, KT1-32, KT1-109, KT1-720, KT1-756) decreased the extent of vascular lesions in the gastric mucosa as revealed by monastral blue 1 min after ethanol. Thus, the mechanism of gastric mucosal protection by these novel aryl sulfhydryl compounds cannot be ascribed to an antisecretory effect, but may be related to prevention of vascular injury.

Protection against Alcohol-Induced Gastric Mucosal Injury by Geranylgeranylacetone: Effect of Indomethacin

The mechanism of gastric mucosal protection by an antiulcer agent, geranylgeranylacetone (GGA), against ethanol-induced injury was investigated. The experiments were conducted with groups of rats with and without intraperitoneal indomethacin pretreatment. Animals received intragastrically either a dose of GGA (200 mg/kg) or a vehicle, followed 30 min later by 1 ml of absolute ethanol. The rats were sacrificed after 30 min and the gastric mucosa was subjected to macroscopic and histologic assessment and the measurements of adherent mucus, its dimension and chemical composition. In the absence of GGA, ethanol produced advanced macroscopic necrosis (greater than 38%) and the extensive necrotic lesions were visible upon histologic examination. Pretreatment with GGA significantly reduced (p less than 0.001) the extent and depth of mucosal necrotic lesions caused by ethanol, and this protection was not thwarted by indomethacin. Evaluation of the adherent mucus and its dimension by Alcian blue uptake and inverted microscope technique revealed that GGA was also capable of preventing the untoward effect of indomethacin on the adherent gastric mucus gel and its thickness. Results of chemical analyses established that in the absence of GGA indomethacin caused an increase in mucus protein (15%) and a decrease in its covalently bound fatty acids (67%) and lipids (36%). The decrease in lipids was particularly reflected in the content of phospholipids. Indomethacin, however, had no apparent effect on the composition of gastric mucus elaborated in the presence of GGA. The results suggest that gastric mucosal protective action of GGA is not mediated by endogenous prostaglandins but rather appears to involve the metabolism of mucosal lipids.

Mechanisms of gastric mucosal protection in peptic ulcer formation

The purpose of this study is to investigate the relationship between gastric mucosal blood flow (GMBF) and hydrogen ion back diffusion (HBD) during the formation of acute gastric mucosal lesion (AGML) induced by intragastric instillation of gastric mucosal barrier breakers such as HCl and/or ethanol in rats. By increasing the concentration of HCl and/or ethanol in the test solution, the decrease in GMBF became evident 5 minutes after the instillation. This decrease was parallel with the simultaneous increase in the HBD and HCO3- secretion together with the increase in AGML in a dose-response manner. These findings indicate that promotion of HBD is in fact related to the decrease of GMBF in AGML induced by HCl and ethanol. Furthermore, to evaluate the mechanism of the cytoprotection, the effects of 16, 16-dimethyl prostaglandin E2 (16, 16-dmPGE2) on decreased GMBF and promoted HBD during impairment of the gastric mucosal barrier were assessed. In addition, the amount of acid (HCl) neutralized by HCO3- secretion, which was included in the decrease in the HBD, was determined. Administration of 16, 16-dmPGE2 markedly inhibited the formation of gastric lesions macroscopically, but had no significant effects on decreased GMBF. Though promotion of HBD was also inhibited dose-dependently, the HBD did not recover to that of the control group not treated by ethanol. HCO3- secretion was increased dose-dependently by administration of 16, 16-dmPGE2, and its maximal secretion was 10% of the decrease in the acid by HBD. These results show that cytoprotection by 16, 16-dmPGE2 is strongly related to factors other than the improvement of GMBF, such as inhibition of HBD and stimulation of HCO3- secretion.