肝硬化患者胃粘膜诱导型一氧化氮合酶定位、定量研究

应用免疫组织化学ＳＰ方法研究肝硬化患者胃粘膜诱导型一氧化氮合酶（ｉＮＯＳ）的表达,探讨一氧化氮（ＮＯ）在肝硬化胃粘膜病变（ＧＭＬ）中的作用。对象与方法一、研究对象乙型肝炎后肝硬化患者４５例,男女比为８∶１,平均年龄５２．８岁（范围２１～６４岁）;肝硬...     

当归多糖对免疫性肝损伤小鼠肝中一氧化氮合酶及凋亡相关基因的影响

目的研究免疫性肝损伤中结构型（ｃＮＯＳ）、诱导型（ｉＮＯＳ）一氧化氮合酶及凋亡相关基因Ｂａｘ、Ｂｃｌ－２表达的变化,在进一步探讨免疫性肝损伤机制的同时观察当归多糖的干预调控作用。方法建立卡介苗和脂多糖诱导的小鼠免疫性肝损伤模型,给予当归多糖 ３０ ｍｇ／ｋｇ、 ６０ ｍｇ／ｋｇ,测定血中 ＡＬＴ、 ＧＳＴ活性及肝中 ＮＯ含量;用免疫组织化学方法观察ｃＮＯＳ、ｉＮＯＳ、Ｂａｘ、Ｂｃｌ－２的表达。结果免疫性肝损伤小鼠ｓＡＬＴ、ｓＧＳＴ及ＮＯ含量明显升高,ｉＮＯＳ含量为正常鼠的１７．８倍,ｃＮＯＳ无明显变化,抗调亡基因Ｂｃｌ－２呈阴性表达,而具有启动凋亡信号、抑制Ｂｃｌ－２表达的 Ｂａｘ增加３１．１％。小剂量当归多糖可使 ｓＡＬＴ、 ｓＧＳＴ及 ＮＯ含量分别降低 ２４．６％、 ４０．８％、 １８．４％, ｉＮＯＳ、Ｂａｘ表达下降８４．２％、 ３７．１％,并使ｃＮＯＳ表达升高６６．８％, Ｂｃｌ－２表达增加 ３．３８倍;大剂量当归多糖可使ｓＡＬＴ、 ｓＧＳＴ及ＮＯ含量分别降低３６．６％、３４．５％、１６、９％,对Ｂａｘ表达的降低作用及对ｃＮＯＳ、Ｂｃｌ－２表达的增加作用不及小剂量明显,但能明显地降低ｉＮＯＳ的表达。结...     

一氧化氮合成酶在支气管哮喘中作用的实验研究

为探讨一氧化氮合成酶（ｎｉｔｒｉｃｏｘｉｄｅｓｙｎｔｈａｓｅ，ＮＯＳ）在实验性大鼠支气管哮喘中的作用，采用３Ｈ－Ｌ－精氨酸转化实验检测鼠肺组织ＮＯＳ活性［１］及还原型辅酶Ⅱ黄递酶（ＮＡＤＰＨ－ｄ）组化染色［２］。结果表明，哮喘组的诱生型ＮＯＳ（ｉＮＯＳ）活性增加１５２．３９％～２４９．４０％，而原生型ＮＯＳ（ｃＮＯＳ）活性则降低６１．８１％～６４．８４％（Ｐ＜０．０５）；致敏组ｉＮＯＳ活性较对照组增加６７．８１％（Ｐ＜０．０５），ｃＮＯＳ活性则无甚改变。ＮＡＤＰＨ－ｄ组化染色显示，哮喘组的气管、细支气管上皮均有整片深着色。哮喘时ｉＮＯＳ活性常呈上调，而ｃＮＯＳ则下调，且ｉＮＯＳ的上调作用尤早于ｃＮＯＳ的下调。提示哮喘时的气道炎症性改变，发生于气道平滑肌收缩及内皮损伤之前。     

慢性胃炎及消化性溃疡诱生型一氧化氮合酶表达和Hp感染的意义

目的探讨一氧化氮在慢性胃炎及消化性溃疡发病机制中的作用，以及ＮＯ和Ｈｐ感染的关系．方法用免疫组化法对正常对照者６例，慢性胃炎５６例及消化性溃疡患者１６例的胃粘膜标本进行检测，观察ｉＮＯＳ表达强度．并用改良Ｇｉｅｍｓａ法同步检测Ｈｐ感染状况．结果ｉＮＯＳ染色定位于胞质，在正常人胃及十二指肠粘膜细胞和腺体均有表达．慢性浅表性胃炎组呈过度表达，其平均表达强度明显高于对照组及慢性萎缩性胃炎组（Ｐ＜００１）．慢性萎缩性胃炎组平均表达水平和对照组比较差异无显著性（Ｐ＞００５）．慢性胃炎组ｉＮＯＳ表达强度与其Ｈｐ分级间呈明显正相关（Ｐ＜００５）．消化性溃疡组平均表达水平较对照组增强（Ｐ＜００５），其ｉＮＯＳ表达强度和Ｈｐ分级间相关性不明显（Ｐ＞００５）．结论ｉＮＯＳ活性增强和过度表达可能在慢性胃炎和消化性溃疡的发病机制中发挥一定作用，并可能是Ｈｐ感染导致慢性胃炎的相关发病机制之一．     

门脉高压性胃病与幽门螺杆菌感染的关系

目的探讨门脉高压性胃病（ｐｏｒｔａｌｈｙｐｅｒｔｅｎｓｉｖｅｇａｓｔｒｏｐａｔｈｙ，ＰＨＧ）与幽门螺杆菌（Ｈｅｌｉｃｏｂａｃｔｅｒｐｙｌｏｒｉ，Ｈｐ）感染之间的关系．方法ＰＨＧ患者６８例，通过内镜检查诊断，胃粘膜活检（每例４块）用Ｗａｒｔｈｉｎ＿Ｓｔａｒｒｙ银染色法检测Ｈｐ．结果ＰＨＧ患者的Ｈｐ阳性率为６０３％（４１／６８），合并消化性溃疡的ＰＨＧ患者Ｈｐ阳性率为５３７％（２２／４１），单纯性ＰＨＧ患者Ｈｐ阳性率为４６３％（１９／４１）．结论ＰＨＧ患者的胃粘膜病变与Ｈｐ感染有密切关系     

肝硬化大鼠内脏血管壁NOS分布的免疫组化研究

目的：观察肝硬化门静脉高压大鼠内脏动、静脉血管壁一氧化氮合酶（ＮＯＳ）的分布及染色强度变化,探讨ＮＯ在门静脉高压形成机制中的作用。方法：采用免疫组化染色法,应用两种ＮＯＳ特异性抗体,分别观察内皮型（ｅＮＯＳ）和诱生型（ｉＮＯＳ）ＮＯＳ的变化特点,并结合计算机图象分析系统对染色强度进行量化处理。结果：肝硬化大鼠肠系膜上动脉（ＳＭＡ）ｉＮＯＳ和ｅＮＯＳ染色强度与对照组相比均显著增加（Ｐ＜０．０１）,其中以ｅＮＯＳ增加更为明显。而两组门静脉（ＰＶ）ＮＯＳ染色强度则无明显差异（Ｐ＞０．０５）。肝硬化组ＳＭＡ的ＮＯＳ染色强度明显高于ＰＶ（Ｐ＜０．０５）。结论：ＮＯＳ在内脏血管表达增多,以及在ＳＭＡ的表达高于ＰＶ,提示ＮＯ可能主要通过扩张内脏动脉、增加内脏血流量而参与门静脉高压的形成。     

大鼠异种原位肝移植急性排斥反应中一氧化氮合酶细胞定位的意义

目的　探讨一氧化氮合酶（ｃＮＯＳ,ｉＮＯＳ） 在金黄地鼠至大鼠异种原位肝移植急性排斥反应中的细胞定位及其意义．方法　我们应用金黄地鼠至大鼠异种原位肝移植急性排斥反应及大鼠同基因原位肝移植动物模型,应用ＮＡＤＰＨ 黄递酶组化染色及免疫组化染色观察移植肝组织ＮＯＳ 的活性及ｃＮＯＳ,ｉＮＯＳ 的蛋白表达．结果　大鼠异种原位肝移植急性排斥反应时血浆ＮＯ 代谢产物ＮＯ－ｘ 明显增高,环孢菌素Ａ 可显著抑制ＮＯ 的合成． 异种肝移植急性排斥反应时,ＮＡＤＰＨ＿ｄ 组化染色及其兔抗大鼠多克隆抗体ｉＮＯＳ,ｃＮＯＳ 免疫组化染色均呈强阳性表达,但以ｉＮＯＳ表达为主．ｉＮＯＳ 主要在肝细胞、肝窦内皮细胞及Ｋｕｐｆｆｅｒ 细胞等炎性细胞表达,而同基因组及免疫抑制治疗组则不表达．结论　原位肝移植肝细胞ＮＯ 产物可随移植肝的免疫状态不同而异,肝细胞ＮＯ 很可能具有重要的免疫保护作用,ＮＯ 合酶及其代谢产物ＮＯ－ｘ 在肝移植急性排斥反应中可具有早期的免疫学监测作用．     

硝酸甘油对哮喘患者一氧化氮内皮素的影响及机制

目的　了解哮喘患者肺泡巨噬细胞（ＡＭ） 、支气管上皮细胞（ＢＥＣ） 源性一氧化氮（ＮＯ）、内皮素（ＥＴ）的分泌状态及硝酸甘油（ＮＴＧ）对哮喘患者ＡＭ、ＢＥＣ产生ＮＯ、ＥＴ的影响及机制。方法　分离纯化了１５ 例轻、中度哮喘发作期患者、７ 名健康受试者ＡＭ、ＢＥＣ,并分为哮喘未干预组、哮喘ＮＴＧ干预组和健康对照组,用放射免疫法和镀铜镉还原法分别测定ＡＭ、ＢＥＣ培养４８ 小时上清液中ＥＴ、ＮＯ·２／ＮＯ·３ 浓度,用原位杂交的方法检测ＡＭ、ＢＥＣｉＮＯＳｍＲＮＡ、ＥＴｍＲＮＡ 的表达。结果　（１） 健康受试者ＡＭ、ＢＥＣ分泌少量ＮＯ和ＥＴ及少量ｉＮＯＳｍＲＮＡ 、ＥＴｍＲＮＡ表达;（２）哮喘患者ＡＭ、ＢＥＣ源性ＮＯ、ＥＴ水平及ＡＭ、ＢＥＣｉＮＯＳｍＲＮＡ、ＥＴｍＲＮＡ表达与各组比较差异有显著性（ Ｐ均＜ ０－０５）;（３）ＮＴＧ 促进哮喘患者ＡＭ、ＢＥＣ源性ＮＯ产生（ Ｐ均＜０－０５）,明显抑制ＥＴ产生和ＥＴｍＲＮＡ 的表达,与对照组比较差异均无显著性（ Ｐ均＞ ０－０５） ,ＮＴＧ同时抑制哮喘患者ＡＭ、ＢＥＣｉＮＯＳｍＲＮＡ的表达,与健康对照组、哮喘未干预组比较差异有显著性（Ｐ均＜０－０５） ;（４） 除哮喘ＮＴＧ     

熊脱氧胆酸促进肝脏部分切除后肝细胞再生

目的 探讨熊脱氧胆酸（ｕｒｓｏｄｅｏｘｙｃｈｏｌｉｃ ａｃｉｄ，ＵＤＣＡ）对胆道梗阻肝脏部分切除（ＰＨ）后肝细胞再生的影响。方法Ｗｉｓｔａｒ大鼠随机分为正常７０％肝部分切除组（Ｎ－ＰＨ）、胆道梗阻２周７０％ＰＨ组（ＢＤＯ－ＰＨ）、ＢＤＯ—ＰＨ ＵＤＣＡ治疗组及ＢＤＯ—ＰＨ生理盐水治疗组。观察肝组织学改变，检测７０％ＰＨ后肝细胞ＢｒｄＵ标记、肝内肝细胞生长因子（ＨＧＦ）及其受体Ｍｅｔ ｍＲＮＡ表达。结果 ＵＤＣＡ治疗能促进胆道梗阻后肝功能好转并减轻肝组织学病变；ＵＤＣＡ治疗组大鼠７０％ＰＨ后肝内ＨＧＦ／Ｍｅｔ ｍＲＮＡ高峰表达值均高于ＢＤＯ—ＰＨ组（Ｐ ＜ ０．０５），肝细胞 ＢｒｄＵ高峰标记指数（５９．３９±１０．８２）％高于 ＢＤＯ—ＰＨ组肝细胞 ＢｒｄＵ高峰标记指数（３６．２２±８．３７％（ｔ＝４．１４９，Ｐ＜０．０１），而与Ｎ－ＰＮ组肝细胞ＢｒｄＵ高峰标记指数（６８．６４±１１．２６％）％相比差异无显著性（ｔ＝１．４５１，Ｐ＞０．０５）。结论 ＵＤＣＡ通过缓解胆道梗阻后肝组织损害并上调７０％ＰＨ后肝内ＨＧＦ／Ｍｅｔ ｍＲＮＡ表达，从而促进胆道梗阻肝脏部分切除后肝细胞再生。     

烧伤大鼠胃组织一氧化氮及一氧化氮合酶的变化

目的研究烧伤后胃组织中一氧化氮（ＮＯ）及两型一氧化氮合酶（ＮＯＳ）的变化规律．方法采用３０％ＴＢＳＡ（ｔｏｔａｌｂｏｄｙｓｕｒｆａｃｅａｒｅａ，ＴＢＳＡ）Ⅲ度烧伤大鼠模型（ｎ＝６４），分别检测伤后１，３，６，１２，２４，４８，７２ｈ胃组织中ＮＯ含量及原生型ＮＯＳ（ｃＮＯＳ）和诱导型ＮＯＳ（ｉＮＯＳ）的活性，并分析ＮＯ含量与两型ＮＯＳ活性之间的关系．结果烧伤后胃组织中ｉＮＯＳ活性与ＮＯ含量的变化趋势一致，伤后３ｈ即显著高于伤前，伤后１２ｈ达峰值，后有所下降但至伤后７２ｈ仍明显高于伤前，二者呈显著正相关（ｒ＝０９４，Ｐ＜００１）．而ｃＮＯＳ活性呈下降趋势，于伤后６ｈ达最低值，后渐回升于伤后７２ｈ基本恢复正常，ｃＮＯＳ与ＮＯ相关不显著（ｒ＝－０５４，Ｐ＞００５）．结论烧伤后胃组织中ＮＯ的变化主要受ｉＮＯＳ活性影响，而ｉＮＯＳ活性上升，ｃＮＯＳ活性下降可能与烧伤后胃的某些病理变化密切相关．     

No additive effect between Helicobacter pylori infection and portal hypertensive gastropathy on inducible nitric oxide synthase expression in gastric mucosa of cirrhotic patients

Increased expression of inducible nitric oxide synthase (iNOS) has been reported in gastric mucosa of patients with Helicobacter pylori infection or portal hypertensive gastropathy (PHG) but whether there is an additive or synergistic impact between H. pylori and PHG on iNOS expression was unknown. Sixty cirrhotic patients and 21 age-matched control subjects without liver disease were included. Biopsies from the gastric antrum and body were obtained for quantitative histological assessment and immunohistochemical staining for iNOS. iNOS staining was detected in endothelial cells and macrophages. In the absence of PHG, H. pylori significantly induced iNOS expression in cirrhotic patients. PHG also significantly induced iNOS expression in H. pylori-negative patients. However, there was no synergistic or additive effect between H. pylori and PHG on this expression. Furthermore, expression of iNOS was significantly higher in patients with severe PHG than in those with mild PHG and without PHG.     

Expression of a 72-kDa heat shock protein, and its cytoprotective function, in gastric mucosa in cirrhotic rats

Background Portal hypertensive gastropathy (PHG) is a clinical entity that is observed frequently in patients with liver cirrhosis. In PHG, gastric mucosa is highly susceptible to mucosal injury caused by noxious agents. Many studies, including ours, have reported that a 72-kDa heat shock protein (HSP72) has a crucial cytoprotective function in gastric mucosa. In this study, we investigated the expression and cytoprotective effect of HSP72 on gastric mucosa in portal hypertensive rats.Methods PHG was produced by bile duct ligation (BDL) or carbon tetrachloride administration in male Sprague-Dawley rats. The expression of HSP72 in the gastric mucosa was evaluated by Western blotting. Induction of gastric mucosal HSP72 by 6-h water-immersion stress was compared between cirrhotic and control rats. Also, mucosal protective abilities against hydrochloric acid (HCl; 0.6N) following pretreatment with water-immersion stress to induce HSP72 were studied in both groups.Results Portal venous pressure was significantly higher in cirrhotic rats compared with control rats (P < 0.05). Baseline expression (before water-immersion stress) of mucosal HSP72 was significantly lower in cirrhotic rats compared with control rats. HCl-induced gastric mucosal lesions were significantly suppressed in control rats compared with cirrhotic rats, especially when HSP72 was preinduced by water-immersion stress.Conclusions These findings suggest that HSP72 in the gastric mucosa plays a crucial role with respect to cytoprotection; the induction of HSP72 may provide therapeutic strategies for protection against mucosal injury in PHG.     

一氧化氮和脂质过氧化物在门脉高压性胃病患者中的变化

背景:胃黏膜糜烂是肝硬化患者发生上消化道出血的重要原因之一。目的:探讨血清和胃黏膜内一氧化氮(NO)和脂质过氧化物(LPO)的变化在门脉高压性胃病(PHG)发病中的作用。方法:将43例PHG患者随机分为两组,20例患者采血清,23例患者取胃黏膜,分别采用硝酸还原法和硫代巴比妥酸(TBA)比色法测定NO和LPO含量。结果:PHG患者血清和胃黏膜内的NO和LPO含量均显著高于对照组(P<0.001)。结论:PHG患者血清和胃黏膜内NO和LPO含量增高可能参与了PHG的发病机制。     

Role of endothelin-converting enzyme-1 in the suppression of constitutive nitric oxide synthase in rat gastric mucosal injury by indomethacin

BACKGROUND: Disturbances in nitric oxide generation and the release of a vasoactive peptide, endothelin-1 (ET-1), are well recognized early events in pathogenesis of NSAID-induced gastropathy. In this study using phosphoramidon, a potent inhibitor of endothelin-converting enzyme-1 (ECE-1), we investigated the influence of ET-1 on the expression of constitutive (cNOS) and inducible nitric oxide synthase (NOS-2) during gastric mucosal injury caused by indomethacin. METHODS: The experiments were conducted with groups of rats pretreated intragastrically with phosphoramidon (10, 20, and 40 mg/kg) or vehicle, followed 30 min later by an intragastric dose of indomethacin (60 mg/kg). The animals were killed 4 h later and their mucosal tissue subjected to macroscopic damage assessment and biochemical measurements. RESULTS: In the absence of phosphoramidon, indomethacin caused extensive multiple hemorrhagic lesions of glandular mucosa, accompanied by a 29.9-fold increase in epithelial cell apoptosis, a 13.3-fold increase in NOS-2 and a 5.5-fold decline in the activity of cNOS, while the mucosal expression of ECE-1 activity increased 4-fold and the level of ET-1 showed a 4.8-fold increase. Pretreatment with phosphoramidon produced dose-dependent reduction in the extent of mucosal damage caused by indomethacin, accompanied by a significant recovery in the expression of cNOS, and a marked decline in ECE-1, epithelial cell apoptosis and the mucosal level of ET-1. Phosphoramidon, however, had no effect on the indomethacin-induced increase in the mucosal expression of NOS-2. CONCLUSIONS: The results suggest that suppression of ET-1 generation counters the mucosal drop in cNOS and the extent of gastric mucosal damage caused by indomethacin, but has no effect on the mucosal responses associated with up-regulation of NOS-2 expression. Hence, only cNOS plays a role in the protection of gastric mucosa against damage by NSAIDs.     

Role of Endothelin-converting Enzyme-1 in the Suppression of Constitutive Nitric Oxide Synthase in Rat Gastric Mucosal Injury by Indomethacin

Background: Disturbances in nitric oxide generation and the release of a vasoactive peptide, endothelin-1 (ET-1), are well recognized early events in pathogenesis of NSAID-induced gastropathy. In this study using phosphoramidon, a potent inhibitor of endothelin-converting enzyme-1 (ECE-1), we investigated the influence of ET-1 on the expression of constitutive (cNOS) and inducible nitric oxide synthase (NOS-2) during gastric mucosal injury caused by indomethacin. Methods: The experiments were conducted with groups of rats pretreated intragastrically with phosphoramidon (10, 20, and 40 mg/kg) or vehicle, followed 30 min later by an intragastric dose of indomethacin (60 mg/kg). The animals were killed 4 h later and their mucosal tissue subjected to macroscopic damage assessment and biochemical measurements. Results: In the absence of phosphoramidon, indomethacin caused extensive multiple hemorrhagic lesions of glandular mucosa, accompanied by a 29.9-fold increase in epithelial cell apoptosis, a 13.3-fold increase in NOS-2 and a 5.5-fold decline in the activity of cNOS, while the mucosal expression of ECE-1 activity increased 4-fold and the level of ET-1 showed a 4.8-fold increase. Pretreatment with phosphoramidon produced dose-dependent reduction in the extent of mucosal damage caused by indomethacin, accompanied by a significant recovery in the expression of cNOS, and a marked decline in ECE-1, epithelial cell apoptosis and the mucosal level of ET-1. Phosphoramidon, however, had no effect on the indomethacin-induced increase in the mucosal expression of NOS-2. Conclusions: The results suggest that suppression of ET-1 generation counters the mucosal drop in cNOS and the extent of gastric mucosal damage caused by indomethacin, but has no effect on the mucosal responses associated with up-regulation of NOS-2 expression. Hence, only cNOS plays a role in the protection of gastric mucosa against damage by NSAIDs.     

Zinc L-carnosine protects against mucosal injury in portal hypertensive gastropathy through induction of heat shock protein 72

BACKGROUND AND AIMS: Increased susceptibility to gastric mucosal injury is observed in portal hypertensive gastropathy (PHG). In this study, the effects of zinc L-carnosine, an anti-ulcer drug, were evaluated on expression of heat shock protein (hsp) 72 and cytoprotection in gastric mucosa in a rat model of PHG. METHODS: Portal hypertensive gastropathy with liver cirrhosis was induced by bile duct ligation for 4 weeks in male Sprague-Dawley rats. Expression of gastric mucosal hsp72 was evaluated by Western blotting at 6 h after intragastric administration of L-carnosine, zinc sulfate, or zinc L-carnosine. Blood was also collected for determination of serum zinc level. Mucosal protective abilities against hydrochloric acid (HCl) (0.6N) followed by pretreatment with L-carnosine, zinc sulfate or zinc L-carnosine were also studied. RESULTS: L-carnosine, zinc sulfate, and zinc L-carnosine induced hsp72 in gastric mucosa of rats with bile duct ligation. Zinc sulfate and zinc L-carnosine suppressed HCl-induced mucosal injury. However, L-carnosine could not suppress HCl-induced mucosal injury. Serum zinc levels were significantly elevated after zinc L-carnosine administration. Furthermore, pretreatment with zinc L-carnosine (30-300 mg/kg) increased the expression of hsp72 in gastric mucosa and prevented HCl-induced mucosal injury in rats with bile duct ligation in a dose-dependent manner. CONCLUSIONS: Zinc derivatives, especially zinc L-carnosine, protected portal hypertensive gastric mucosa with increased hsp72 expression in cirrhotic rats. It is postulated that zinc L-carnosine may be beneficial to the mucosal protection in PHG as a 'chaperone inducer'.     

热休克蛋白70对肝硬化门静脉高压性胃病大鼠胃黏膜损伤的保护作用

背景:临床上重度门静脉高压性胃病(PHG)常可引起上消化道致命性大出血。热休克蛋白70(HSP70)是加强胃黏膜防御功能的主要热休克蛋白。目的:探讨HSP70对肝硬化PHG大鼠胃黏膜损伤的保护作用及其机制。方法:以CCl_4制备肝硬化PHG大鼠模型,实验分为正常对照组、PHG组和三组热处理组。以酶联免疫吸附测定(ELISA)检测胃黏膜HSP70和肿瘤坏死因子(TNF)-α水平,并观察胃黏膜病理变化。结果:与正常对照大鼠相比,PHG大鼠胃黏膜HSP70水平明显降低而TNF-α水平明显升高,胃黏膜出现明显病理损伤;热处理组正常大鼠胃黏膜HSP70水平明显升高,TNF-α水平无变化,胃黏膜无明显损伤。与PHG大鼠相比,热处理组PHG大鼠胃黏膜HSP70水平明显升高,TNF-α水平明显降低,胃黏膜损伤明显减轻。结论:HSP70能减轻肝硬化PHG大鼠胃黏膜损伤,其保护作用可能与胃黏膜TNF-α水平降低有关。     

Role of endothelin-1 and constitutive nitric oxide synthase in gastric mucosal resistance to indomethacin injury: effect of antiulcer agents.

BACKGROUND: Endothelin-1 (ET-1) and nitric oxide, recognized key mediators implicated in the pathophysiology of gastric mucosal injury, are known to exert opposing effects on the inflammatory processes mediated by regulatory cytokines. In this study we investigated the mucosal expression of ET-1 and interleukin-4 (IL-4) and the activity of constitutive nitric oxide synthase (cNOS) during indomethacin-induced gastric mucosal injury and evaluated the effect of antiulcer agents, omeprazole and sucralfate, on this process. METHODS: The experiments were conducted with groups of rats pretreated intragastrically with omeprazole (40 mg/kg), sucralfate (200 mg/kg), or vehicle, followed 30 min later by an intragastric dose of indomethacin (60 mg/kg). The animals were killed 2 h later, and their mucosal tissue subjected to macroscopic damage assessment, ET-1 and IL-4 expression assay, and the measurement of cNOS activity. RESULTS: In the absence of antiulcer agents, indomethacin caused multiple hemorrhagic lesions and extensive epithelial cell apoptosis, accompanied by a 20.7% reduction in IL-4, a 3.1-fold increase in mucosal expression of ET-1, and a 4.2-fold decrease in cNOS. Pretreatment with a gastroprotective agent, sucralfate, produced a 59.7% reduction in the mucosal damage caused by indomethacin, a 41.2% decrease in epithelial cell apoptosis, and a 56.5% reduction in ET-1, whereas the expression of IL-4 increased by 29.3% and that of cNOS showed a 3.3-fold increase. In contrast, the pretreatment with a proton pump inhibitor, omeprazole, led to only a 10.5% reduction in the extent of mucosal damage caused by indomethacin and a 13% decrease in apoptosis, whereas the expression of cNOS increased by 68.7% and ET-1 by 12.2%, and the level of IL-4 remained essentially unchanged. CONCLUSIONS: The results suggest that an increase in the vasoconstrictive ET-1 level combined with a decrease in regulatory cytokine, IL-4, and a loss of compensatory action by cNOS may be responsible for the gastric mucosal injury caused by indomethacin. Our findings also indicate the value of sucralfate in countering the untoward gastrointestinal side effects of nonsteroidal anti-inflammatory drug therapy.     

Overexpressed nitric oxide synthase in portal-hypertensive stomach of rat: A key to increased susceptibility to damage?

BACKGROUND & AIMS: Portal hypertension predisposes gastric mucosa to increased injury. The aim of this study was to determine whether overexpression of constitutive nitric oxide synthase (cNOS) is responsible for increased susceptibility of portal-hypertensive (PHT) gastric mucosa to damage. METHODS: In gastric specimens from PHT and sham-operated rats, cNOS messenger RNA expression was determined by Northern blotting and cNOS protein expression by Western blotting, immunohistochemistry, and enzyme activity assay. Extent of ethanol- induced gastric mucosal necrosis, mucosal blood flow, and gastric NOS activity in PHT and sham-operated rats was determined after administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) or saline. RESULTS: cNOS messenger RNA level, cNOS enzyme activity, and fluorescence signals for cNOS were increased significantly in PHT rats compared with controls. Inhibition of overexpressed cNOS by L-NAME (5 mg/kg) significantly reduced ethanol-induced mucosal necrosis and normalized blood flow in PHT gastric mucosa, whereas this dose of L- NAME significantly increased mucosal necrosis in sham-operated rats. CONCLUSIONS: Portal hypertension activates the cNOS gene with overexpression of cNOS protein in endothelia of gastric mucosal vessels. Excessive NO production by overexpressed cNOS may play an important role in the increased susceptibility of PHT gastric mucosa to damage. (Gastroenterology 1997 Jun;112(6):1920-30)