三叶肽对胃黏膜适应性细胞保护的调节作用

目的探讨三叶肽(ITF)对胃黏膜适应性细胞保护的调节作用。方法采用重复水浸束缚应激(WRS)法制作模型，动态监测模型动物的胃黏膜血流量(GMBF)，观察黏膜损伤指数(UI)及病理组织学变化；采用逆转录-聚合酶链反应(RT—PCR)和蛋白质免疫印迹法(Western blot)检测乳癌相关肽(PS2)、诱导型一氧化氮合酶(iNOS)、ITF、转化生长因子-α(TGF—α)及环氧合酶-2(COX-2)的表达。结果单次WRS后造成胃黏膜广泛损伤；重复应激后胃黏膜产生适应性，GMBF上升，损伤逐渐减轻；经4次应激后，UI降低到单次应激的22．0％，并且胃腺区细胞增殖。单次应激后，PS2基因表达减弱，而iNOS、ITF、TGF—α及COX-2基因表达均增强；重复应激后，PS2、ITF、TGF—α表达逐渐增强，而iNOS及COX-2基因表达逐渐减弱；正常时iNOS、ITF及COX-2几乎无表达，PS2、ITF、TGF—α主要在胃腺颈部表达；应激后PS2、ITF、TGF—α不但在胃腺颈部黏膜增殖带表达增强。在胃腺基底部亦有表达，iNOS及COX-2在溃疡及其边缘存在。结论胃黏膜适应性细胞保护伴有细胞增殖，PS2、ITF、TGF—α表达逐渐增强，iNOS及COX-2表达逐渐减弱，表明三叶肽在这一现象中具有重要的调节作用。     

环氧合酶-2在应激胃黏膜适应性细胞保护中的作用

目的：研究环氧合酶-2(COX-2)、乳癌相关肽(PS2)、诱导型一氧化氮合酶(iNOS)在水浸束缚应激(WRS)大鼠胃黏膜基因中表达的变化，探讨其在应激胃黏膜适应性细胞保护中的相互关系及作用。方法采用重复WRS制作模型，动态监测胃黏膜血流量(GMBF)，大体及光镜下观察黏膜损伤程度(UI)及组织学变化，逆转录-多聚酶链反应(RT-PCR)和Western blot检测COX-2、PS2，及iNOS表达变化。结果：单次应激造成胃黏膜广泛损伤，重复应激后胃黏膜产生适应性，胃黏膜血流量上升，损伤逐渐减轻，4次应激后，损伤指数降低为单次应激的21．99％，并且胃腺区细胞增殖。单次应激后，PS2表达减弱，而COX2及iNOS增强；重复应激后，PS2基因表达逐渐增强，而COX-2及iNOS基因表达逐渐减弱；正常时，COX-2及iNOS几乎无无达，PS2主要在胃腺颈部表达；应激后，PS2不但在胃腺颈部黏膜增殖带表达增强，在胃腺基底部亦有表达，COX-2及iNOS在溃疡及其边缘存在。结论：胃黏膜适应性细胞保护伴有细胞增殖，PS2表达逐渐增强，COX2及iNOS表达逐渐减弱，表明三者在这一现象中重要的调节作用。     

解痉多肽在应激胃黏膜适应性保护中的作用

目的 研究解痉多肽(spasmolytic polypeptide,SP)在水浸束缚应激(WRS)大鼠胃黏膜的基因表达变化,探讨其在应激胃黏膜适应性保护中的作用.方法 采用单次和重复水浸束缚应激制作模型,动态监测胃黏膜血流量(GMBF),大体及光镜下观察黏膜损伤程度(UI)及组织学变化,逆转录-多聚酶链反应(RT-PCR)检测研究SP基因表达变化,免疫组化染色进一步证实SP表达.结果 ①单次应激造成胃黏膜广泛损伤,但损伤指数在3、5、7 d逐渐减小,至7 d降为208%,GMBF逐渐恢复,至7 d上升为正常94.5%,SP基因表达逐渐增强(0.50±0.12 vs 0.71±010,P＜0.01),免疫组化染色计分为0.94±0.10 vs 1.50±0.13 (P＜0.01);②重复应激后胃黏膜产生适应性,胃黏膜血流量上升,损伤逐渐减轻,4次应激后,损伤指数降低为单次应激的22%,胃黏膜血流量上升为正常94.2%,并且胃腺区细胞增殖,SP基因表达增强(0.57±0.01 vs 0.97±003,P＜0.01),免疫组织化学染色计分为1.25±0.11 vs 2.56±0.16(P＜0.01).结论 SP可能参与了应激胃黏膜适应性细胞保护.     

应激状态下大鼠胃黏膜适应性细胞保护作用的研究

目的：探讨心理、一氧化氮合酶（NOS）及胃黏膜血流量（GMBF）与应激状态下大鼠胃黏膜适应性细胞保护相互作用及意义。方法：采用高压恒流脉冲刺激器复制胃黏膜损伤模型，将72只雄性SD大鼠随机分为对照组、规则光组及不规则光组3组，分光光度法检测NOS活性，动态检测GMBF及Nils Lambecht法判定胃黏膜损伤指数（Ⅱ）。结果：在两个应激组中，NOS均升高，GMBF均下降后回升，而黏膜损伤均渐趋减轻。在规则组中，Ⅱ与GMBF呈显著负相关，在不规则组中，Ⅱ与NOS和GMBF均呈显著负相关，而NOS与GMBF呈显著正相关。结论：NOS、GMBF及心理共同参与了胃黏膜适应性细胞保护反应。     

低氧诱导因子1α在大鼠应激性溃疡中的表达及其意义

目的:探讨低氧诱导因子1α(HIF-1α)在大鼠应激性溃疡发生发展中的表达及意义。方法:应用浸水-束缚应激(WRS)方法建立大鼠应激性溃疡模型。依据不同浸水时间,将42只雄性SD大鼠随机(随机数字法)分为0h(正常对照)组、2h(W2)组、4h(W4)组、6h(W6)组、8h(W8)组、12h(W12)组、16h(W16)组,每组各6例,通过测定各组大鼠应激后胃液pH值、胃黏膜血流量(GMBF)、胃黏膜损伤指数(Guth评分),观察胃黏膜肉眼大体观,Western blot检测各组大鼠胃黏膜组织中HIF-1α、血管内皮生长因子(VEGF)的表达水平,探究HIF-1α在大鼠应激性溃疡发生发展中的作用。结果:与对照组比较,水浸应激后胃液pH值、GMBF明显降低(P<0.01)、Guth评分逐渐增加(P<0.01),水浸应激8h均达到峰值,之后随着浸水时间的延长,胃液pH值、GMBF逐渐升高,Guth评分逐渐下降。与对照组比较,随着浸水时间延长,HIF-1α、VEGF表达增加(P<0.05),浸水8h时间点达到高峰(P<0.05)。与W8组比较,W12、W16组HIF-1α、VEGF表达分别有所下降(P<0.05);与W6组比较,W12、W16组HIF-1α、VEGF表达差异无统计学意义(P>0.05)。结论:应激性溃疡发生发展中,胃黏膜缺血缺氧损伤越严重,HIF-1α、VEGF表达量增加,以促进黏膜新生血管生成,促使机体适应并改善缺氧环境。     

幽门螺杆菌根除对不同胃黏膜病变环氧合酶-2表达的影响

目的探讨Hpylori根除对慢性浅表性胃炎和萎缩肠化胃黏膜上皮细胞COX-2表达的影响。方法采用快速尿素酶试验和组织学碱性品红染色法检测胃黏膜Hpylori感染状况;应用免疫组织化学法检测胃黏膜上皮细胞COX-2的表达。结果17例Hpylori阳性慢性浅表性胃炎中11例见不同程度胃黏膜上皮细胞COX-2阳性表达,Hpylori根除后6例COX-2表达消失,2例减弱,2例无改变,1例增强,前后对照差异有显著性(P<0.05)。同时Hpylori根除后12例胃黏膜慢性炎症见不同程度减轻,与COX-2表达变化有较好相关性(P<0.05)。10例Hpylori感染萎缩性胃炎伴肠化生者9例COX-2表达阳性,Hpylori根除后1、2a复查COX-2表达减弱5例,消失2例,1例无变化,1例增强,前后对照差异有显著性(P<0.05),但胃黏膜组织学对照无明显改善。结论根除Hpylori可消除慢性浅表性胃炎胃黏膜上皮细胞COX-2表达,且与慢性炎症程度消退相关。而根除Hpylori虽可减弱萎缩肠化胃黏膜上皮细胞COX-2表达,但不能改善胃黏膜萎缩和肠化状态。     

三叶因子2和环氧合酶-2在胃癌组织中的表达

目的:研究三叶因子2(TFF2)和环氧合酶-2(COX-2)在正常胃黏膜组织、癌旁组织和胃癌组织中的表达情况,探讨TFF2表达与胃癌发生的关系。方法:采用SP免疫组化方法检测30例正常胃黏膜组织、50例癌旁组织和50例胃癌组织中TFF2和COX-2的表达。结果:正常胃黏膜组织→癌旁组织→胃癌组织中,TFF2表达呈逐渐减弱趋势(165.80±16.42,184.44±19.02和206.79±17.62,P<0.01),而COX-2的表达呈逐渐上升趋势(217.50±12.60,203.08±17.68和193.50±16.160,P<0.01),TFF2的表达强度与COX-2呈负相关(r=-0.761,P<0.01)。结论:COX-2的表达增加抑制TFF2的表达,细胞增殖与凋亡失衡,最终导致胃癌的发生。     

环氧化酶-2在胃溃疡和胃癌的表达及与幽门螺杆菌感染的关系

目的探讨环氧化酶-2(COX-2)在幽门螺杆菌(Hp)感染与非感染性胃溃疡及胃癌的表达。方法选择绵阳市404医院消化内科2011年2月-2012年2月的门诊及住院患者,用免疫组织化学方法检测196例经胃镜和组织病理学检查明确为胃溃疡(病理分型:肠上皮化生、异型增生)、胃癌及正常胃黏膜者的胃黏膜COX-2蛋白的表达,比较各病理分类之间及Hp感染与非感染之间COX-2蛋白表达的差异。结果胃溃疡(肠上皮化生、异型增生)、胃癌组的炎症细胞、腺上皮细胞、癌细胞及极少量正常黏膜上皮细胞中有COX-2表达。从正常胃黏膜-胃溃疡(肠上皮化生、异型增生)-胃癌COX-2的阳性表达有逐渐增强的趋势(P<0.05)。Hp阳性组COX-2的阳性表达高于Hp阴性组(P<0.05),胃癌组COX-2的阳性表达高于胃溃疡组(P<0.05)。结论 COX-2在胃癌的表达高于胃溃疡。Hp感染可诱导COX-2过度表达。     

中西医结合治疗应激性溃疡的进展

应激性溃疡 (stress ulcer,SU )是严重创伤 (包括大手术 )、感染、休克、烧伤、中枢性系统损伤、梗阻性黄疸等危重症的常见并发症 ,应激情况下可继发胃、十二指肠等黏膜发生糜烂、溃疡 ,主要临床表现为消化道出血 ,病情严重者预后危险。近年来 ,国内外学者对其发病机制及采用中西医结合治疗进行了一系列的实验与临床研究 ,取得了较大的进展 ,现就其研究现状进行综述。1　发病机制1.1　胃黏膜保护因素减弱 :胃黏膜血流量减少和微循环障碍可引起细胞物质及能量代谢紊乱 ,细胞结构和完整性遭破坏而致胃黏膜损伤 〔1 ,2〕。许多应激性因素致胃…     

下丘脑白介素-6对应激性溃疡大鼠胃黏膜损伤的影响

目的 探讨下丘脑白介素-6对应激性溃疡大鼠胃黏膜血流量、胃液pH值和胃黏膜损伤的影响.方法 采用液压打击法建立大鼠颅脑外伤应激性溃疡模型.20只雄性SD大鼠在长征医院神经外科大鼠实验房饲养1周后开始实验.大鼠被随机(随机数字法)等分为对照组、致伤1 h组、致伤6h和致伤12 h组,采用免疫组化、Western blot等方法检测致伤后下丘脑性白介素-6的表达与分布.同时,检测各组大鼠胃液pH值、胃黏膜血流量、胃黏膜损伤指数,并观察胃黏膜大体及光镜下组织病理学变化.结果 白介素-6免疫反应阳性细胞广泛分布于应激大鼠下丘脑水平的神经细胞中,在室旁核(paraventricular rucleus,PVN)附近分布尤为密集.致伤后1h胃液pH值明显降低,致伤后6 h处于最低点(与1 h组比较P＜0.05).致伤后1 h即出现胃黏膜损伤,并且胃黏膜损伤指数随时间的延长而不断增加;致伤后1 h有血流量的暂时性增加,处于波峰,6 h后趋于平稳.大体及镜下病理均提示,胃黏膜呈应激性溃疡改变.结论 在液压打击致应激性溃疡的SD大鼠中,下丘脑白介素-6可通过PVN的介导激活神经内分泌代谢,引发胃黏膜损伤.     

Therapeutic potential of 1-methylnicotinamide against acute gastric lesions induced by stress: role of endogenous prostacyclin and sensory nerves

1-Methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit antithrombotic and antiinflammatory actions. However, it is not yet known whether MNA affects gastric mucosal defense. The effects of exogenous MNA were studied on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and water restraint stress (WRS) or in rats administered 75% ethanol. MNA [6.25-100 mg/kg intragastrically (i.g.)] led to a dose-dependent rise in the plasma MNA level, inhibited gastric acid secretion, and attenuated these gastric lesions induced by WRS or ethanol. The gastroprotective effect of MNA was accompanied by an increase in the gastric mucosal blood flow and plasma calcitonin gene-related peptide (CGRP) levels, the preservation of prostacyclin (PGI(2)) generation (measured as 6-keto-PGF1alpha), and an overexpression of mRNAs for cyclooxygenase (COX)-2 and CGRP in the gastric mucosa. R-3-(4-Fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO 324479), which is the selective antagonist of IP/PGI(2) receptors, reversed the effects of MNA on gastric lesions and GBF. MNA-induced gastroprotection was attenuated by suppression of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; SC-560] and COX-2 [4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one; rofecoxib] activity, capsaicin denervation, and by the pretreatment with CGRP(8-37) or capsazepine. Addition of exogenous PGI(2) or CGRP restored the MNA-induced gastroprotection in rats treated with COX-1 and COX-2 inhibitors or in those with capsaicin denervation. WRS enhanced MDA content while decreasing superoxide dismutase (SOD) activity in the gastric mucosa, but pretreatment with MNA reversed these changes. MNA exerts potent gastroprotection against WRS damage via mechanisms involving cooperative action of PGI(2) and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation.     

Lansoprazole induces mucosal protection through gastrin receptor-dependent up-regulation of cyclooxygenase-2 in rats

Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2- one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE2 and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.     

Induction of cyclooxygenase-2 in rat gastric mucosa by rebamipide, a mucoprotective agent

Recent studies indicate an expression of mitogen-inducible cyclooxygenase (COX-2) in gastric mucosa. Rebamipide, a mucoprotective agent enhances prostaglandin (PG) synthesis. The present study was designed to clarify the mechanism for rebamipide-induced mucosal protection. Male Sprague-Dawley rats were administered 5, 15, or 50 mg/kg/day rebamipide for 14 days. The expression of constitutive cyclooxygenase (COX-1) and COX-2 in gastric mucosa was determined using Western blot analysis. Another series of rats was used to examine 1) the levels of PGE(2) in stomach with and without pretreatment with a COX-2 inhibitor; 2) the protective action of rebamipide against gastric damage caused by 0.6 N HCl; and 3) the effects of a COX-2 inhibitor on rebamipide-induced gastric mucosal protection. COX-2 expression was enhanced, whereas COX-1 expression did not change significantly in the gastric mucosa of rats after treatment with rebamipide. The gastric mucosal PGE(2) was higher in the rebamipide groups than in the vehicle-treated group. Rebamipide also suppressed gastric damage induced by HCl in a dose-dependent manner. A COX-2 inhibitor blocked the rebamipide-induced increase in mucosal PGE(2), and mucosal protection induced by rebamipide. The results indicate that rebamipide induces COX-2 expression, increases PGE(2) levels, and enhances gastric mucosal defense in a COX-2-dependent manner. Thus, COX-2 has an important role in the effects of rebamipide on gastric mucosal protection.     

Prostaglandin/cyclooxygenase pathway in ghrelin-induced gastroprotection against ischemia-reperfusion injury

Ghrelin is involved in the control of food intake, but its role in gastroprotection against the formation of gastric mucosal injury has been little elucidated. We studied the effects of peripheral (i.p.) and central (i.c.v.) administration of ghrelin on gastric secretion and gastric mucosal lesions induced by 3 h of ischemia/reperfusion (I/R) with or without inhibition of ghrelin growth hormone secretagogue type 1a receptor (GHS-R1a) by using ghrelin antagonist, d-Lys(3)-GHRP-6; blockade of cyclooxygenase (COX)-1 (indomethacin, SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole]) and COX-2 (rofecoxib); and bilateral vagotomy or capsaicin denervation. I/R produced typical gastric erosions, a significant fall in the gastric blood flow (GBF), an increase in gastric myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) content, and the up-regulation of mucosal ghrelin mRNA. Ghrelin dose-dependently increased gastric acid secretion and significantly reduced I/R-induced gastric erosions, while producing a significant rise in the GBF and mucosal PGE(2) generation and a significant fall in MPO activity and MDA content. The protective and hyperemic activities of ghrelin were significantly attenuated in rats pretreated with d-Lys(3)-GHRP-6 and capsaicin denervation and completely abolished by vagotomy. Indomethacin, SC560, and rofecoxib, selective COX-1 and COX-2 inhibitors, attenuated ghrelin-induced protection that was restored by supplying the methyl analog of prostaglandin (PG) E(2). The expression of mRNA for COX-1 was unaffected by ghrelin, but COX-2 mRNA and COX-2 protein were detectable in I/R injured mucosa and further up-regulated by exogenous ghrelin. We conclude that ghrelin exhibits gastroprotective and hyperemic activities against I/R-induced erosions, the effects that are mediated by hormone activation of GHS-R1a receptors, COX-PG system, and vagal-sensory nerves.     

Lafutidine,a novel histamine H2-receptor antagonist,increases serum calcitonin gene-related peptide in rats after water immersion-restraint stress

Lafutidine is a novel histamine H(2)-receptor antagonist with a potent and long-lasting anti-acid secretory effect that has also been found to have a potent gastroprotective effect. We investigated the effect of lafutidine on gastric mucosal injury induced in rats with the use of water-immersion restraint stress (WRS) by examining serum calcitonin gene-related peptide (CGRP) concentrations, which we measured with the use of an enzyme immunometric assay. WRS-induced mucosal erosive injury in the stomach was reduced significantly by both lafutidine and famotidine pretreatment (from 7.79 +/- 2.02 mm(2) to 3.09 +/- 0.74 mm(2) and 4.05 +/- 1.18 mm(2), respectively). A single administration of lafutidine or famotidine did not change the serum CGRP concentration from the control value when these drugs were administered without WRS. Lafutidine pretreatment before WRS caused a significant increase in serum CGRP concentration compared with famotidine (lafutidine, 86.64 +/- 9.52 pg/mL; famotidine, 47.55 +/- 4.35 pg/mL; control, 58.43 +/- 6.07 pg/mL). Our results suggest that lafutidine augments CGRP release from the rat stomach when administered before the induction of WRS.     

Ulcerogenic influence of selective cyclooxygenase-2 inhibitors in the rat stomach with adjuvant-induced arthritis

Cyclooxygenase (COX)-2 inhibitors have been developed as new gastric sparing anti-inflammatory drugs. We previously reported that the ulcerogenic response to conventional nonselective COX inhibitors, such as indomethacin and aspirin, was markedly increased in arthritic rats. The ulcerogenic effect of selective COX-2 inhibitors in arthritic animals, however, remains unknown. The present study was designed to examine the influence of selective COX-2 inhibitors, such as rofecoxib and celecoxib, on gastric mucosal integrity in rats with adjuvant-induced arthritis. Arthritis was induced in male dark Agouti rats by injection of Freund's complete adjuvant into the right hind paw. Two weeks after the injection, the animals were fasted for 18 h, various COX inhibitors were administered orally, and the mucosa was examined for lesions 4 h later. Oral administration of indomethacin caused hemorrhagic gastric lesions in both normal and arthritic rats, although the severity of lesions was significantly greater in the latter group. In contrast, neither rofecoxib nor celecoxib caused any gastric damage in normal rats, but both drugs provoked hemorrhagic gastric lesions in arthritic rats. The expression of COX-2 mRNA and immuno-positive cells was observed in the gastric mucosa of arthritic but not normal rats. The gastric mucosal prostaglandin (PG) E(2) content was significantly elevated in arthritic rats in a rofecoxib-sensitive manner. In conclusion, COX-2 inhibitors produce gastric lesions in arthritic rats, similar to the nonselective COX-inhibitors. COX-2 is up-regulated in the stomach of arthritic rats, and PGs produced by COX-2 play a role in maintaining the integrity of the gastric mucosa.     

Interaction of cyclooxygenase isoenzymes, nitric oxide, and afferent neurons in gastric mucosal defense in rats

The cyclooxygenase (COX)-2 inhibitors 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5II)-furanone (DFU) (0.02-2 mg/kg) and N-[2-(cyclohexyloxy)-4-nitrofenyl]-methanesulfonamide (NS-398) (0.01-1 mg/kg), the COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (0.05-5 mg/kg), and dexamethasone (1 mg/kg) were studied in rats challenged with intragastric acid (300 mM HCl). All compounds induced severe gastric damage when rats were treated concurrently with the inhibitor of constitutive and inducible nitric-oxide (NO) synthase N(G)-monomethyl-L-arginine methyl ester (L-NAME) (3 or 40 mg/kg). DFU and NS-398 caused significantly less damage in rats receiving the selective inhibitor of inducible NO synthase N-(3-(aminomethyl)benzyl)acetamidine (1400W) (0.3 mg/kg). The COX-1 inhibitor SC-560 induced moderate damage in the acid-challenged stomach even without suppression of NO, but damage was aggravated by L-NAME. The COX-3 inhibitor phenacetin (400 mg/kg) did not injure the gastric mucosa despite suppression of NO. Furthermore, DFU, NS-398, SC-560, and dexamethasone caused severe injury in the acid-challenged stomach of rats pretreated with capsaicin to ablate afferent neurons. The mucosal damage induced by the COX-1 inhibitor, the COX-2 inhibitors, and dexamethasone in L-NAME- or capsaicin-treated rats was reversed by coadministration of 16,16-dimethyl-prostaglandin E2 (2 x 8 ng/kg). Gross mucosal damage was paralleled by histology. Our results support the concept that endogenous NO, prostaglandins, and afferent neurons act in concert in the regulation of gastric mucosal integrity. The prostaglandins necessary for mucosal defense in the face of NO suppression, and afferent nerve ablation can be derived either from COX-1 or COX-2. The data do not propose a protective role for a phenacetin-sensitive COX-3. Our findings suggest that not only COX-1 but also COX-2 has important functions in the maintenance of gastric integrity.     

In vivo study on cross talk between inducible nitric-oxide synthase and cyclooxygenase in rat gastric mucosa: effect of cyclooxygenase activity on nitric oxide production

The integrity of gastric mucosa during endotoxemia is maintained by the balance of inflammatory mediators, such as prostanoids originated from cyclooxygenase-2 (COX-2) and nitric oxide (NO) from inducible nitric-oxide synthase (iNOS). Thus, we elucidated in vivo cross talk between prostanoids and NO in gastric mucosa during endotoxemia, using an iNOS-specific inhibitor, N-(3-(aminomethyl)benzyl)acetamidine (1400W); a nonspecific COX inhibitor, indomethacin; and a COX-2-specific inhibitor, N-(2-[cyclohexyloxy]-4-nitrophenyl)methanesulfonamide (NS-398). Gastric mucosal NO and prostaglandin E2 (PGE2), a predominant product of COX, expressed as mean +/- S.D. of five rats per group, were assayed by electron paramagnetic resonance spectrometry and enzyme immunoassay technique, respectively. The levels of NO and PGE2 increased gradually up to 6 h after administration of bacterial lipopolysaccharide (LPS) (NO: control, 0.35 +/- 0.16; 6 h, 13.3 +/- 3.3 nmol/g tissue/30 min; and PGE2: control, 288 +/- 16; 6 h, 806 +/- 15 pg/g tissue). Pretreatment with 1400W decreased the increase in NO level without any effect on the PGE2 level (NO, 4.0 +/- 0.4 nmol/g tissue/30 min; PGE2, 788 +/- 26 pg/g tissue). In contrast, treatment with indomethacin and NS-398 inhibited not only PGE2 level but also NO level in a dose-dependent manner without any significant effect on both iNOS and COX protein and mRNA expression. These results demonstrate that in the LPS-treated rat gastric mucosa, PGE2 enhances the release of NO after activation of iNOS, although NO produced by iNOS does not stimulate the release of PGE2 by COXs. The effect of COX activity on iNOS-NO pathway can be important in the regulation of gastric mucosal integrity in inflammatory states.