表皮生长因子对胃粘膜保护作用的机理初探

报道表皮生长因子（ＥＧＦ）保护胃粘膜抵制损伤的作用。实验采用多普勒激光流量仪测定ＧＭＢＦ，将ＳＤ鼠随机分成两组（移出内源性ＥＧＦ组和未移出组）并应用不同剂量外源性ＥＧＦ，观察其对ＧＭＢＦ和胃损伤的影响。结果显示：移出组加重酒精诱发的胃损伤（Ｐ＜０．０５），对ＧＭＢＦ虽有所下降，但无统计学意义。在预先加用外源性ＥＧＦ织，胃粘膜损伤减轻，ＧＭＢＦ增加（二者Ｐ＜０．０５），而且ＧＭＢＦ增长与ＥＧＦ剂量（从３．２５μｇ～２５μｇ）呈正相关，相关系数ｒ＝０．６８，Ｐ＜０．００１；与损伤指数呈负相关，ｒ＝－０．７５，Ｐ＜０．００１。因此本文结论是ＥＧＦ对粘膜的保护可能是通过完整的ＧＭＢＦ所介导。     

Effects of Ebrotidine on Aspirin-Induced Gastric Mucosal Damage and Blood Flow in Humans

Nonsteroidal anti-inflammatory agents (NSAIDs) such as aspirin (ASA) damage the gastric mucosa both in normal subjects and in arthritic patients. The aim of this study was to investigate the protective action of a new H₂-receptor antagonist, ebrotidine, in the prevention of ASA-induced acute mucosal injury in the stomach of healthy volunteers. In a double-blind randomized crossover study 10 male volunteers received treatment with either placebo plus ASA (500 mg) or ebrotidine (800 mg) plus ASA twice daily for 3 days with 10 days' washout period between treatments. The mean number of gastric erosions seen at endoscopy after treatment with ebrotidine plus ASA (2.0 ± 0.3) was significantly lower than that after placebo plus ASA (3.7 ± 0.2). This reduction in lesion core by ebrotidine was accompanied by a significant increase in gastric blood flow (by 15% in corpus and 26% in antrum), by a rise in transmucosal potential difference (by 12%), and by a decrease of mucosal microbleeding. Ebrotidine afforded substantial protection from ASA-induced injury to the gastric mucosa, and this was accompanied by increase of the mucosal blood flow. We conclude that ebrotidine provides mucosal protection for patients taking NSAIDs     

Gastric Mucosal Blood Flow and Neutrophil Activation in Aspirin-Induced Gastric Mucosal Damage in Man

Konturek JW, Dembinski A, Stoll R, Konturek M, Domschke W. Gastric mucosal blood flow and neutrophil activation in aspirin-induced gastric mucosal damage in man. Scand J Gastroenterol 1993; 28:767-771.

Gastric and intestinal injury induced by nonsteroidal anti-inflammatory agents (NSAIDs) such as aspirin (ASA) is a common side effect of this class of drugs, but the mechanism by which these drugs act is not fully explained. In this study the effects of 3 days of continuous oral ASA administration (1 g twice daily) to eight healthy male volunteers were studied. To estimate the extent of mucosal damage, gastroscopy was performed before and after 3 days of ASA treatment, during which the mucosal blood flow was measured by means of laser-Doppler flowmetry. Before each endoscopy gastric microbleeding was measured. Since neutrophil activation has recently been suggested to be involved in the pathogenesis of ASA-induced gastric mucosal damage, we examined the influence of ASA treatment on the activation of leukocytes by determining their association with platelets in the blood. Aspirin-induced acute gastric damage reached about 3.5 in the endoscopic Lanza score. Mucosal blood flow increased significantly after ASA treatment, by about 50% in the oxyntic gland area and by 87% in the antral area. Gastric microbleeding rose from about 0.38 ml/day in the intact stomach to about 7.7 ml/day after ASA treatment. The platelet/neutrophil adherence increased significantly in both thrombin-unstimulated and thrombin-stimulated platelets. We conclude that acute 3 days' administration of ASA in man produces well-defined areas of gastric damage accompanied by a significant increase in gastric microbleeding and gastric blood flow and that ASA promotes platelet/neutrophil adhesion that may resemble the neutrophil/ endothelium interaction in the gastric mucosa.     

Gastric Mucosal Stripping in the Dog

Aagaard, P., Andreassen, M., Simonsen, J., Olsen, J., Funding, J. & Fernandez, A. 1972. Gastric Mucosal Stripping in the Dog. Scand. J. Gastroent. 7, 219–224.

Stripping of the gastric mucosa in an area corresponding to 50–75% of the body of the stomach was performed in 13 dogs. The stripping was done deep to the muscularis mucosae. Preoperatively the augmented histamine test was carried out. The dogs were followed for up to 16 months after the operation, and throughout this period the acid output was reduced. Autopsy revealed in the stripped area a low epithelium with a reduced number of parietal and pepsin-producing cells. There were no signs of fibrosis with shrinkage. After the operation some dogs had a fairly considerable weight loss. It has not been finally elucidated whether this operation is applicable in the treatment of duodenal ulcer in man.     

氨水对大白鼠胃粘膜长期作用的影响：胃粘膜屏障功能的变化

本实验使用0.01％及0.02％的氨水,以自由饮水的形式经口长期喂养大白鼠,观察了氨水对胃粘膜血流、胃粘膜电位差及胃粘膜前列腺素E_2的影响。结果表明:由HP分泌的悄素酶所分解产生的氨长期作用于胃粘膜,可以导致大白鼠的胃粘膜血流和前列腺E_2减少,使胃粘膜电信差降低,破坏胃粘膜的防御机能,可能是HP导致慢性胃炎及胃溃疡的一个重要因素。     

电针足阳明经穴对胃粘膜损伤大鼠胃粘膜血流量及生长抑素的影响

目的 :观察电针足阳明经“四白”、“天枢”、“足三里”穴对胃粘膜损伤大鼠胃窦和延髓内生长抑素(SS)含量的影响及与胃粘膜损伤、胃粘膜血流量的关系 ,以探讨经脉 -脏腑相关的物质基础。方法 :健康 SD大鼠 6 0只 ,随机分为正常对照组 (对照组 ) ,模型组 ,针刺四白组、天枢组及非穴点组共 6组 ,以乙醇灌胃造成胃粘膜损伤大鼠模型 ,观察电针大鼠足三里、天枢、四白穴对胃粘膜血流量 (氢气清除法 )的影响 ,用放免分析法检测大鼠胃窦及延髓 SS含量。结果 :胃粘膜血流量在胃粘膜损伤后明显降低 ,针刺四白、天枢、足三里及非穴点后 ,均有不同程度升高 ,尤以足三里和四白组升高明显 (P<0 .0 1) ;胃窦及延髓 SS模型组较对照组升高 (P<0 .0 5 ,<0 .0 1) ,而针刺四白、足三里组升高不明显 (P>0 .0 5 )。结论 :胃窦、延髓 SS含量变化与胃粘膜血流量的改变有一定关系 ,电针足阳明经四白、足三里穴可能通过对胃窦及延髓 SS含量的改变来影响胃粘膜血流量 ,促进胃粘膜损伤的修复。     

胃痛灵对大鼠胃粘膜血流量及脾虚大鼠模型的影响

为深入探讨胃癌灵保护胃粘膜的作用机制，研究了胃痛灵（WTL）对无水乙醇损伤大鼠胃粘膜血流量（GMBF）、脾虚大鼠D-木糖吸收率、胃壁结合粘液量以及胃酸分泌和胃蛋白酶活性的影响。结果显示WTL能够明显增加大鼠GMBF（P＜0．05）、胃壁结合粘液量（P＜0．05），提高脾虚大鼠D-木糖吸收率（P＜0．05），增强胃粘膜防御机能，但对脾虚大鼠胃酸的分泌和胃蛋白酶活性均无明显影响。在体外也无中和胃酸的能力。     

Enhanced Gastric and Duodenal Platelet-Activating Factor and Leukotriene Generation in Duodenal Ulcer Patients

Background: Primary hosts of Helicobacter heilmannii are domestic animals-cats, dogs and pigs, but rarely is it detected in gastric biopsies from humans. We found H. heilmannii in gastric biopsies obtained from patients living in a predominantly rural area. Methods: We evaluated geographic and demographic data from the area and calculated both the total prevalence and the prevalence in each community in this area. Chi-squared test and exploratory data analysis were used for statistical evaluation. Histologic and clinical data were recorded. Results: Forty-three communities, mostly rural, were identified in the area, the size of which is about 200 km². H. heilmannii was detected in 33 patients (prevalence 2%) living in 20 communities. The prevalence of H. heilmannii statistically significantly varied in those communities from 0.06%-1.1%. It was possible to infer that there is a negative correlation between prevalence and community size. Chronic active gastritis was diagnosed in all patients. The active inflammation became inactive after eradication of H. heilmannii via common anti-Helicobacter therapy. Conclusion: A high prevalence of H. heilmannii-associated gastritis in a small, predominantly rural area and statistically significant differences in prevalence from one community to the next, i.e. highest in the smallest village and lowest in a small town with a rather urban lifestyle, were found. In our opinion, these prevalence rates may be a consequence of transmission of the infection from domestic animals, because animal-human contact is generally more common in villages than in towns.     

Effect of Acetyl Salicylic Acid and Cetraxate on Human Gastric Mucosal Blood Flow: Clinical Application of Laser Doppler Measurement

Abstract: The effects of acetyl salicylic acid and cetraxate on gastric mucosal blood flow (GMBF) were examined in human subjects. GMBF was determined endoscopically using a laser Doppler flowmeter. The normal value in 16 adults ranged from 1.7 ± 0.8 volts (mean ± SD) at the lesser curvature of the antrum to 3.72 ± 0.79 volts at the greater curvature of the body. In four normal volunteers, the time course of GMBF was measured after the oral intake of 0.5 g acetyl salicylic acid with or without cetraxate. GMBF was significantly lower after intake of acetyl salicylic acid at 15 min at the lesser curvature of the body (3.6 ± 1.0 to 2.3 ± 0.7, P<0.05) and at 20 min at the lesser curvature of the antrum (2.7 ± 0.6 to 1.4 ± 0.2, P<0.05), as compared with the values at 5 min. This adverse effect of acetyl salicylic acid on GMBF was inhibited by concomitant administration of 0.8 g cetraxate. It was concluded that cetraxate prevented the acetyl salicylic acid induced decrease in GMBF.     

Acute Gastric Mucosal Lesion in the Aged

Abstract: Over a period of 3 years between August 1985 and July 1988, 110 patients (male/female ratio, 64: 46, age range 22–89 years, mean 48.1 years) were diagnosed endoscopically as having acute gastric mucosal lesion (AGML). These patients were divided into an elderly group (60 years or more, 26 patients) and a younger group (less than 60 years, 84 patients). The chief complaint, the precipitating factors, the location of the lesion, the disease type, the background gastric mucosa and the state of bleeding were compared between the groups. AGMLs in elderly patients were found to have the following characteristic features. The chief complaints included hematemesis and melena, and oral drugs were the precipitating factor in many patients. The lesion often occurred in the body or whole area of the stomach, and was found to be relatively rare in the vestibule. An acute gastric ulcer was the most frequent clinical finding. The background gastric mucosa was rated C-II or more severe in most cases. Overt bleeding was present in many cases, requiring endoscopic hemostasis.     

Effect of Vitamin E on Aspirin-Induced Gastric Mucosal Injury in Rats

We investigated the effect of vitamin E on aspirin-induced gastric mucosal injury in rats. Twenty-eight male Sprague-Dawley rats were divided into four groups and were fed for 20 weeks with a diet containing <0.1 mg/100 g of -tocopherol (vitamin E-deficient), 2 mg/100 g of -tocopherol (normal and vitamin E-sufficient), or 50 mg/100 g of -tocopherol (vitamin E-supplemented). In vitamin E-deficient rats, oral administration of aspirin (200 mg/kg) plus HCl created more severe hemorrhagic erosions than in other rats. Vitamin E-deficient rats had higher levels of thiobarbituric acid reactive substances, myeloperoxidase activity, and cytokine-induced neutrophil chemoattractant in the gastric mucosa. Flow cytometry showed that CD18 expression on stimulated neutrophils was higher in vitamin E-deficient rats than in vitamin E-supplemented rats. These results suggest that vitamin E protects against aspirin-induced gastric mucosal injury by inhibiting lipid peroxidation and accumulation of activated neutrophils.     

丹参对肝硬变犬门脉压力及胃粘膜血流的影响

通过胆总管结扎法，制造犬肝硬变门脉高压模型，并直接测定丹参注射液对肝硬变犬门脉压力及胃粘膜血流（GMBF）的影响。结果表明，静注丹参注射液后，肝硬变犬的门脉压力（PpV）、嵌塞肝静脉压（WHVP）、肝静脉压力梯度（HVPG）显著下降（P＜0．01），平均动脉压（MAP）、心率（HR）无显著变化（P＞0．05）。给药后10min，肝硬变及正常犬的GMBF显著增加（P＜0．05）．用药后30min达最高值（P＜0．01），60min后GMBF稍有下降．但与用药前比较仍有显著差异（P＜0．05）。说明丹参在降低肝硬变犬门脉压力的同时改善GMBF，对血压、心率无显著影响。为副作用小，兼具降低门脉压力与保护胃粘膜作用的药物。     

Gastric Mucosal Blood Flow Before and After TAE

Abstract: An evaluation of gastrointestinal complications after transcatheter arterial embolization (TAE) was conducted by endoscopy in order to investigate the pathogenesis of post TAE gastrointestinal complications. In addition, the gastric mucosal blood flow (GMBF) was evaluated by a laser doppler. The incidence of complications following the administration of a H₂–blocker was 34.1%, whereas the incidence following the administration of PGE1 and without medication were 2.3% (P >0.01) and 9.4%, respectively. In the group which did not receive medication, just after a TAE the GMBF decreased markedly in the lesser curvature of the gastric antrum (P >0.01), and in the lesser and greater curvature of the gastric body. This persisted from 1 to 7 days after the TAE with the GMBF showing a tendency to recover. On the other hand, in the group who received PGE1, the GMBF did not decrease in any site of the stomach following TAE. These findings suggested that the ischemia which occurred due to a decrease in the GMBF caused the gastrointestinal complications seen.     

Gastric Mucosal Protection by Aegle Marmelos Against Gastric Mucosal Damage: Role of Enterochromaffin Cell and Serotonin

Background/Aims:

Serotonin (5-hydroxytryptamine; 5-HT) released from enterochromaffin (EC) cells in gastric mucosa inhibits gastric acidity by increasing the gastric mucus secretion. In the present study, we evaluated the effect of aqueous extract of Aegle marmelos (AM) ripe fruit pulp (250 mg/kg body weight) on mean ulcer index (MUI), EC cells, 5-HT content, and adherent mucosal thickness of ulcerated gastric tissue in adult albino rats.

Material and Methods:

Ulceration was induced by using aspirin (500 mg/kg, p.o.), cerebellar nodular lesion and applying cold-restraint stress.

Results:

In all cases increased MUI in gastric tissue along with decreased EC cell count was observed with concomitant decrease of 5-HT content and adherent mucosal thickness (P < 0.05). Pretreatment with AM for 14 days decreased MUI, increased EC cell count, and 5-HT content as well as adherent mucosal thickness in all ulcerated group (P < 0.05).

Conclusion:

AM produces gastric mucosal protection mediated by increased EC cell count and 5-HT levels.     

Role of Platelet-Activating Factor in Acid-Induced Esophageal Mucosal Injury

Studies on the pathophysiology of reflux esophagitis have focused on the associated motility and/or structural abnormalities, with relatively little attention directed to inflammatory mediators involved in the acid-induced mucosal injury. Mast cells line the subepithelial lamina propria in both humans and the opossum model, and are ideally positioned to respond to luminal agents that cross the mucosal barrier. To determine whether certain mast cell mediators are involved in acid-induced mucosal injury, epithelial injury scores following 60 min of luminal perfusion of the opossum esophagus with 100 mM HCl were compared in the presence and absence of two different mast cell stabilizers (disodium cromoglycate and doxantrazole) or the selective platelet-activating factor antagonist TCV-309. In control animals acid perfusion caused release of PAF and significant epithelial injury, characterized by epithelial sloughing and cleft formation. This injury was unaffected by pretreatment with disodium cromoglycate or doxantrazole but was completely prevented by TCV-309 (histology damage score, 2.40±0.28 in controls vs 0.50 ± 0.14 in TCV-309-treated animals). These studies suggest that platelet-activating factor is an important mediator of acid-induced esophageal mucosal damage.     

The pH Measurement of Fasting Gastric Juice in Acute Gastric Mucosal Lesions

Abstract: Fasting gastric juice acidity was assessed to elucidate its role in the cause of acute gastric mucosal lesions (AGML). Gastric juice was aspirated through an auxiliary endoscopic channel during routine endoscopic examinations, and its pH was measured with a glass electrode PH meter. The pH of 100 cases with AGML (acute hemorrhagic erosions (AHE), acute gastric ulcer and acute hemorrhagic gastritis), and 586 cases with other ulcerative or inflammatory lesions were compared with the gastric juice pH in 1775 endoscopically normal subjects. The pH value was classgied into four acid groups: Hyperacidity (pH < 1.4), Normoacidity (1).5 < pH < 2.0), Hypoacidity (2).1 < pH <4.0) and Anacidity (4). 1 < pH). In cases with AHE, a signifcant hyperacidity was recognized both in the periods preceding and just after the onset. This hyperacidity was followed by signgicant anacidity, and thereafter a return to normoacidity. These pH changes coincided well with endoscopic appearances; preceding stage-hypernormacidity, black-slough stage—hyperacidity, white-slough stage-anacidity and scarring stage-;normoacidity. These results suggest that an elevation of gastric acidity etiologically relates with the formation of AGML, especially Shin.     

Preventive Effects of Rebamipide on NSAID-Induced Gastric Mucosal Injury and Reduction of Gastric Mucosal Blood Flow in Healthy Volunteers

The precise mechanisms of acute damage and the role of gastric mucosal blood flow in gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) remain uncertain. The aim of this study was to evaluate the preventive effect of rebamipide on gastric mucosal injury and reduction of gastric mucosal blood flow (GMBF) after ibuprofen administration. Twenty healthy volunteers were randomized two groups. The rebamipide group took ibuprofen, 1800 mg/day, and rebamipide, 100 mg t.i.d., for 7 days. The placebo group took ibuprofen, 1800 mg/day. The numbers of gastric ulcer subjects were three in the placebo group and zero in the rebamipide group. The mean modified Lanza score after ibuprofen administration was significantly higher in the placebo group than the rebamipide group (2.9±1.7 vs. 1.3±1.0, respectively; P=0.032). The GMBF of the placebo group was significantly decreased at antrum from baseline, from 2.8±0.5 to 2.0±0.5 tissue perfusion units (P=0.005). There was no difference in GMBF change in the rebamipide group. Gastric mucosal injury was correlated with GMBF reduction in antrum (r=−0.677, P=0.001). In conclusion, it is suggested that the decrease in GMBF may have been associated with NSAID-induced gastric mucosal injury, and rebamipide may have prevented NSIAD-induced gastric mucosal injury by maintaining GMBF in healthy subjects.     

Aspirin-Induced Mucosal Cell Death in Human Gastric Cells: Role of a Caspase-Independent Mechanism

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of pain and inflammation. Their use may result in gastroduodenal side effects, such as gastric irritation and ulcer formation. Although various strategies have been employed to minimize these adverse effects induced by NSAIDs, effective therapeutic targeting of this problem has been prevented by an incomplete understanding of the mechanisms underlying their pathogenesis. This study was undertaken to determine the role that non-caspase-mediated apoptosis plays in inducing cellular injury and death in gastric mucosa exposed to aspirin. We proposed that the responsible mechanism was through mitochondrial failure, increased mitochondrial membrane permeability, and translocation of the intramitochondrial protein apoptosis-inducing factor (AIF). Human gastric adenocarcinoma mucosal cells (AGS cells) received no pretreatment or were preincubated with caspase inhibitors for 30 min. Cells were then treated with 40 mM aspirin for 2–4 h. Apoptosis was assessed by measuring the DNA–histone complex formation. Cell viability was determined by an acridine orange–ethidium bromide (EtBr) assay. The activation of AIF was evaluated by both Western blotting of the cytosol and mitochondrial extracts as well as by visualization and staining using fluorescence microscopy. Results showed that caspase inhibitor preincubation decreased DNA–histone complex formation when compared to aspirin treatment alone. Based on light microscope visualization, however, we determined that caspase inhibitor preincubation was unable to prevent AGS cell damage and death. These findings were confirmed by the acridine orange–EtBr test, which showed decreased cell viability with caspase inhibitor preincubation and aspirin treatment. We then tested whether non-caspase-mediated cell death occurred through an AIF mitochondrial pathway using Western blotting and fluorescence microscopy to determine AIF activation. The results showed that untreated cells had AIF localized to the mitochondria and cytosol. With 40 mM ASA at 4 h, translocation of AIF from the mitochondria to the nucleus occurred, showing activation. Caspase inhibition with z-VAD was unable to prevent AIF localization to the nucleus and subsequently unable to prevent cell death. Our results indicate that ASA in the presence of caspase inhibitors causes gastric mucosal cell death through a caspase-independent pathway suggestive of apoptosis-like programmed cell death. Effective therapeutic targeting of aspirin-induced apoptosis likely requires inhibition of both mitochondrial and caspase-mediated pathways.     

老年胃溃疡患者粘膜血流量和粘膜电位的变化

胃粘膜血流量(GMBF)在消化性溃疡的发生、发展和愈合过程中起着重要作用,胃粘膜电位(GMPD)为检测胃粘膜结构完整性的指标。我们于1988年1～6月对40例各期老年胃溃疡患者的GMBF和GMPD进行了检测,现报告如下。病例选择与方法一、病例选择 (一)老年胃溃疡组共40例,其中男性30例,女性10例,年龄60～75岁,平均64.5