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      雷貝拉唑?qū)SAIDs相關(guān)小腸損傷大鼠緊密連接蛋白Occludin表達(dá)的影響及其機(jī)制

      2012-09-14 04:50:00張振玉吳海露胡可偉姜宗丹楊小兵王勁松
      關(guān)鍵詞:雙氯貝拉酚酸

      高 欣,張振玉,吳海露,胡可偉,姜宗丹,楊小兵,王勁松

      南京醫(yī)科大學(xué)附屬南京第一醫(yī)院1.消化科;2.病理科,江蘇 南京 210006

      雷貝拉唑?qū)SAIDs相關(guān)小腸損傷大鼠緊密連接蛋白Occludin表達(dá)的影響及其機(jī)制

      高 欣1,張振玉1,吳海露1,胡可偉1,姜宗丹1,楊小兵2,王勁松2

      南京醫(yī)科大學(xué)附屬南京第一醫(yī)院1.消化科;2.病理科,江蘇 南京 210006

      目的 探討雷貝拉唑?qū)Ψ晴摅w類(lèi)抗炎藥(NSAIDs)相關(guān)性小腸損傷大鼠緊密連接蛋白Occludin表達(dá)的影響及可能的機(jī)制。方法 將36只SD大鼠隨機(jī)平均分為陰性對(duì)照組、雙氯酚酸損傷組和雷貝拉唑處理組。采用雙氯酚酸7.5 mg/(kg·d)灌胃,連續(xù)4 d,制造大鼠NSAIDs相關(guān)性小腸損傷模型;而雷貝拉唑處理組在每次造模前0.5 h予以15 mg/(kg·d)雷貝拉唑灌胃處理,連續(xù)4 d。處死大鼠進(jìn)行大體及病理觀察小腸損傷情況,采用免疫組織化學(xué)和Western blot方法檢測(cè)小腸組織中Occludin和磷酸化ERK(p-ERK)蛋白表達(dá)水平的變化。結(jié)果 雷貝拉唑處理組大鼠大體和病理?yè)p傷均低于損傷組(P<0.05)。Occludin蛋白在損傷組中表達(dá)較對(duì)照組明顯下降(P<0.05),而在雷貝拉唑處理組中的表達(dá)較損傷組上升(P<0.05);與陰性對(duì)照組相比,p-ERK蛋白在損傷組中表達(dá)上升(P<0.05),在雷貝拉唑處理組中的表達(dá)較損傷組下降(P<0.05)。結(jié)論 雷貝拉唑?qū)Υ笫驨SAIDs相關(guān)性損傷有保護(hù)作用,其機(jī)制可能是通過(guò)MAPK中的ERK途徑,增加小腸上皮組織中Occludin蛋白表達(dá),從而增強(qiáng)腸黏膜屏障功能。

      雷貝拉唑;NSAIDs相關(guān)性小腸損傷;Occludin蛋白;MAPK/ERK信號(hào)通路

      非甾體抗炎藥(NSAIDs)臨床應(yīng)用日趨廣泛,NSAIDs相關(guān)性消化道反應(yīng)也日益受到關(guān)注,但長(zhǎng)期以來(lái),NSAIDs相關(guān)性小腸損傷一直被人們忽視。近年來(lái),隨著膠囊內(nèi)鏡和雙氣囊小腸鏡檢查的普及,研究已發(fā)現(xiàn)NSAIDs相關(guān)的小腸損傷在使用NSAIDs患者中發(fā)生并不罕見(jiàn),損傷程度甚至超過(guò)了胃損傷[1]。質(zhì)子泵抑制劑(PPI)對(duì)NSAIDs相關(guān)性胃黏膜損傷有很好的保護(hù)作用,而對(duì)NSAIDs相關(guān)性小腸損傷的影響則存在一定爭(zhēng)議。本實(shí)驗(yàn)旨在研究雷貝拉唑?qū)Υ笫驨SAIDs相關(guān)性小腸損傷及其緊密連接蛋白Occludin表達(dá)的影響,并探討其可能的機(jī)制。

      1 材料與方法

      1.1 材料 2個(gè)月齡體質(zhì)量180~200 g的健康雄性SD大鼠30只(由南京醫(yī)科大學(xué)附屬南京第一醫(yī)院動(dòng)物實(shí)驗(yàn)中心提供);雷貝拉唑鈉腸溶片(商品名:信衛(wèi)安,產(chǎn)品批號(hào):110503)由上海信誼藥廠有限公司饋贈(zèng),雙氯酚酸鈉雙釋放腸溶膠囊(商品名:戴芬,產(chǎn)品批號(hào):91184)購(gòu)自德國(guó)Temmler Werke GmbH公司,兩種藥物均溶于生理鹽水中,經(jīng)超聲乳化后制成懸濁液;磷酸化 ERK(p-ERK)、Occludin抗體購(gòu)自 cell signal公司。

      1.2 方法

      1.2.1 動(dòng)物分組:將30只大鼠隨機(jī)分為3組,每組10只:1組,陰性對(duì)照組;2組,雙氯酚酸損傷組;3組,雷貝拉唑處理組。

      1.2.2 動(dòng)物造模:除陰性對(duì)照組外,其他兩組大鼠按照雙氯酚酸7.5 mg/kg劑量進(jìn)行灌胃,1次/d,連續(xù)4 d,制造大鼠急性胃黏膜損傷模型。每次造模前0.5 h,雷貝拉唑處理組予15 mg/kg劑量雷貝拉唑進(jìn)行灌胃,1次/d,其余組大鼠同時(shí)予以等體積生理鹽水灌胃,連續(xù)給藥4 d。以上所有大鼠每次灌胃液體量均按10 mL/kg計(jì)算。末次灌胃后所有大鼠禁食不禁水18 h,以10%水合氯醛按3 mL/kg行腹腔注射麻醉處死動(dòng)物,取小腸組織。

      1.2.3 大體觀察及損傷評(píng)分:沿腸系膜對(duì)側(cè)切開(kāi)小腸,PBS沖洗干凈后,于解剖顯微鏡(10×)下觀察,按照修改后的Reuter方法進(jìn)行小腸損傷情況評(píng)分:未見(jiàn)明顯損傷為0分;局灶性充血,但未見(jiàn)潰瘍形成為1分;有潰瘍形成,但無(wú)充血及腸管增厚為2分;潰瘍形成伴炎性反應(yīng)(一處)為3分;潰瘍形成伴炎癥反應(yīng)(兩處及兩處以上)為4分;當(dāng)主要病變部位長(zhǎng)度在1~2 cm之間為5分;當(dāng)主要病變部位長(zhǎng)度>2 cm時(shí)為6分;當(dāng)腸管出現(xiàn)輕度粘連(很容易解除的粘連)時(shí)計(jì)分增加1分,出現(xiàn)明顯粘連時(shí)計(jì)分增加2分。

      1.2.4 組織學(xué)觀察及病理學(xué)計(jì)分:將小腸組織4%中性甲醛固定24 h,經(jīng)常規(guī)脫水、透明、石蠟包埋切片,HE染色,光鏡下觀察小腸組織的病理學(xué)變化,按照Chiu方法進(jìn)行病理?yè)p傷評(píng)分:0分(腸黏膜絨毛正常);1分(絨毛頂端上皮下出現(xiàn)囊狀間隙,伴毛細(xì)血管充血);2分(上皮下間隙擴(kuò)大,固有層中度水腫,中央乳糜管擴(kuò)張);3分(固有層明顯水腫,腸黏膜上皮層細(xì)胞變性壞死,少數(shù)絨毛頂端上皮脫落);4分(上皮層細(xì)胞變性壞死、脫落,部分絨毛脫落,固有層裸露,毛細(xì)血管擴(kuò)張、充血);5分(絨毛脫落,固有層崩解,出血或潰瘍形成)。

      1.2.5 Occludin免疫組織化學(xué)染色:采用 Envision法,石蠟切片脫蠟至水,蛋白酶E 37℃ 10 min消化,PBS沖洗,加 Occludin抗體(1∶60)4℃過(guò)夜,PBS沖洗,加Envision二抗37℃ 30 min,PBS沖洗,DAB顯色,鏡下控制顯色時(shí)間,蘇木精復(fù)染、脫水、透明、樹(shù)膠封片。觀察染色為棕褐色的陽(yáng)性細(xì)胞的百分比進(jìn)行綜合判定:陽(yáng)性細(xì)胞數(shù)<10%為陰性(-),10% ~20%為弱陽(yáng)性(+),20% ~50%為中等陽(yáng)性(++),>50%為強(qiáng)陽(yáng)性(+++)。

      1.2.6 Western blot分析:取約 100 mg 小腸組織,加入蛋白裂解液,4℃裂解,10 000 r/min離心15 min,取上清為全蛋白提取物,將蛋白提取物與蛋白上樣緩沖液混合,煮沸5 min,分裝保存于-80℃冰箱。進(jìn)行SDS-PAGE凝膠電泳、轉(zhuǎn)膜,封閉后加入一抗4℃過(guò)夜。再加入辣根過(guò)氧化物酶標(biāo)記的二抗,孵育后ECL法顯色于X光片后照相,以β-actin作為內(nèi)參照,使用Image J 1.44p軟件分析目的蛋白條帶灰度值與內(nèi)參照β-actin條帶灰度值的比值,作為目的蛋白相對(duì)表達(dá)量。

      1.3 統(tǒng)計(jì)學(xué)處理 采用SPSS v17.0軟件進(jìn)行處理及分析,各組損傷指數(shù)以中位數(shù)表示,統(tǒng)計(jì)數(shù)據(jù)采用兩個(gè)獨(dú)立樣本的秩和檢驗(yàn),統(tǒng)計(jì)量采用Mann-Whitney U檢驗(yàn);Western blot實(shí)驗(yàn)數(shù)據(jù)用x-±s表示,統(tǒng)計(jì)數(shù)據(jù)采用兩個(gè)獨(dú)立樣本的t檢驗(yàn);P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

      2 結(jié)果

      2.1 各組大鼠小腸組織大體及病理學(xué)觀察

      2.1.1 大體觀察:陰性對(duì)照組大鼠小腸組織未見(jiàn)明顯損傷;雙氯酚酸損傷組小腸損傷較重,腹腔內(nèi)可見(jiàn)腸管粘連、水腫、擴(kuò)張,小腸黏膜可見(jiàn)多處散發(fā)充血、糜爛及片狀潰瘍;而雷貝拉唑處理組腸管粘連及水腫不明顯,小腸黏膜可見(jiàn)少量散在點(diǎn)狀糜爛及小潰瘍。

      2.1.2 病理觀察:陰性對(duì)照組黏膜上皮結(jié)構(gòu)完整,形態(tài)正常,未見(jiàn)潰瘍及糜爛;雙氯酚酸損傷組小腸絨毛結(jié)構(gòu)消失,可見(jiàn)壞死、糜爛及潰瘍形成,固有層可見(jiàn)炎細(xì)胞浸潤(rùn),部分黏膜上皮結(jié)構(gòu)完全破壞;而雷貝拉唑處理組也可見(jiàn)部分壞死及潰瘍形成,但較損傷組明顯減輕,大部分黏膜上皮結(jié)構(gòu)尚完整。

      2.1.3 大體及病理學(xué)損傷評(píng)分:雙氯酚酸損傷組大體和病理評(píng)分明顯高于陰性對(duì)照組(P=0.000);雷貝拉唑處理組大體和病理評(píng)分與損傷組相比均降低,差異具有統(tǒng)計(jì)學(xué)意義(P<0.05,見(jiàn)表1)。

      2.2 小腸組織Occludin蛋白免疫組織化學(xué)染色 根據(jù)免疫組織化學(xué)染色結(jié)果,陰性對(duì)照組中Occludin蛋白分布于小腸黏膜上皮細(xì)胞膜,呈表達(dá)強(qiáng)棕褐色信號(hào),強(qiáng)陽(yáng)性表達(dá)率為60%(6/10);損傷組Occludin蛋白表達(dá)明顯減弱,呈低表達(dá),強(qiáng)陽(yáng)性表達(dá)率為10%(1/10);雷貝拉唑處理組可觀察到Occludin蛋白的棕褐色信號(hào)表達(dá)較損傷組高,強(qiáng)陽(yáng)性表達(dá)率為40%(4/10)(見(jiàn)圖1、表2)。

      2.3 Western blot檢測(cè)小腸組織Occludin和p-ERK蛋白表達(dá)水平 損傷組小腸組織Occludin蛋白的表達(dá)明顯低于對(duì)照組(P<0.05),而雷貝拉唑處理組Occludin蛋白的表達(dá)高于損傷組(P<0.05);損傷組中p-ERK蛋白的表達(dá)明顯高于對(duì)照組(P<0.05),而雷貝拉唑處理組p-ERK蛋白的表達(dá)低于損傷組(P<0.05,見(jiàn)圖 2、表 3)。

      表1 各組大鼠小腸組織大體及病理?yè)p傷計(jì)分中位數(shù)比較(n=10)Tab 1 Comparison of general and pathological injury scores in each group(n=10)

      圖1 各組小腸組織Occludin蛋白免疫組織化學(xué)染色表達(dá)水平(100×)A:陰性對(duì)照組;B:雙氯酚酸損傷組;C:雷貝拉唑處理組Fig 1 Expression of Occludin protein immunohistochemical staining in each group(100×) A:negative control group;B:cliclofenal injury group;C:Kabeprazole treated group

      表2 各組免疫組織化學(xué)胃黏膜組織Occludin蛋白表達(dá)水平Tab 2 Comparison of expression of Occludin protein immunohistochemical staining in each group

      圖2 各組小腸組織Occludin和p-ERK蛋白Western blot表達(dá)結(jié)果 1:陰性對(duì)照組;2:雙氯酚酸損傷組;3:雷貝拉唑處理組Fig 2 ExpressionResultsof Occludin and p-ERK protein for small intestinal tissue in each group by Western blot 1:negative control group;2:diclofenal injury group;3:rabeprazole treated group

      表3 各組大鼠小腸組織 Occludin/β-actin和p-ERK/β-actin表達(dá)水平比較(±s)Tab 3 Comparison of Occludin/β-actin and p-ERK/β-actin expression for rat intestinal tissue in each group(±s)

      表3 各組大鼠小腸組織 Occludin/β-actin和p-ERK/β-actin表達(dá)水平比較(±s)Tab 3 Comparison of Occludin/β-actin and p-ERK/β-actin expression for rat intestinal tissue in each group(±s)

      與陰性對(duì)照組相比,*P<0.05;與雙氯酚酸損傷組相比,#P<0.05

      組別Occludin p-ERK陰性對(duì)照組0.55 ±0.13 0.20 ±0.04雙氯酚酸損傷組 0.07 ±0.03* 1.31 ±0.12*雷貝拉唑處理組 0.42 ±0.08# 0.53 ±0.06#

      3 討論

      近來(lái)有研究發(fā)現(xiàn),質(zhì)子泵抑制劑(PPI)不僅能夠減少胃酸分泌,而且具有抗炎抗氧化的作用[2]。研究表明,PPI對(duì)NSAIDs相關(guān)性胃損傷具有保護(hù)作用[3-5],而對(duì)NSAIDs相關(guān)性小腸損傷的影響并未取得統(tǒng)一意見(jiàn):有部分研究者認(rèn)為,PPI對(duì)NSAIDs相關(guān)性小腸損傷具有保護(hù)作用,其中以蘭索拉唑、雷貝拉唑效果較明顯[6-8];另有部分研究者卻發(fā)現(xiàn),PPI與NSAIDs合用時(shí)對(duì)小腸的損傷較單用NSAIDs時(shí)更嚴(yán)重[9-10]。臨床中NSAIDs經(jīng)常需要與PPI聯(lián)用,因此明確PPI對(duì)NSAIDs相關(guān)性小腸損傷的影響對(duì)指導(dǎo)臨床用藥具有很大的意義。

      本實(shí)驗(yàn)參考了陳漢卿等[8]以雙氯酚酸制造大鼠NSAIDs相關(guān)性小腸損傷模型的方法,減少雙氯酚酸的用藥時(shí)間(由5 d減少為4 d),實(shí)驗(yàn)過(guò)程中未發(fā)現(xiàn)有大鼠提前死亡的情況,處死后亦可觀察到大鼠明顯的小腸損傷,造模成功。實(shí)驗(yàn)結(jié)果發(fā)現(xiàn),與損傷組相比,雷貝拉唑處理組大鼠小腸的大體和病理?yè)p傷情況均明顯減輕(P<0.05)。因此,在本實(shí)驗(yàn),我們認(rèn)為雷貝拉唑?qū)SAIDs相關(guān)性小腸損傷有保護(hù)作用。

      Occludin蛋白是緊密連接中最重要的組成蛋白之一,對(duì)緊密連接的構(gòu)成、黏膜屏障的維持起關(guān)鍵作用。在腸黏膜上皮中,當(dāng)Occludin蛋白表達(dá)發(fā)生變異、減少、缺失時(shí),可導(dǎo)致腸黏膜屏障功能障礙,黏膜通透性增高,從而引起小腸黏膜損傷[11-12]。本實(shí)驗(yàn)中,在雙氯酚酸損傷后,大鼠小腸組織中Occludin蛋白表達(dá)明顯下降,而經(jīng)過(guò)雷貝拉唑處理的大鼠,Occludin蛋白則較損傷組上調(diào)表達(dá),與大體及病理結(jié)果一致,提示雷貝拉唑的保護(hù)作用與上調(diào)小腸黏膜中Occludin蛋白表達(dá)有關(guān)。

      細(xì)胞外信號(hào)調(diào)節(jié)激酶/絲裂原活化蛋白激酶通路(ERK/MAPK)是經(jīng)典的細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)途徑,具有調(diào)節(jié)細(xì)胞增殖、分化、凋亡等多重功能。ERK/MAPK信號(hào)通路在NSAIDs相關(guān)性消化道損傷過(guò)程中扮演重要角色,ERK/MAPK信號(hào)通路的激活參與了NSAIDs相關(guān)性胃腸道損傷的過(guò)程[13-14]。另有研究[15-16]發(fā)現(xiàn),ERK信號(hào)通路對(duì)包括Occludin在內(nèi)的多種緊密連接蛋白的表達(dá)起到重要的調(diào)節(jié)作用,ERK蛋白能夠通過(guò)自身磷酸化的過(guò)程調(diào)控Occludin蛋白的表達(dá),進(jìn)而影響?zhàn)つて琳瞎δ堋=Y(jié)合本實(shí)驗(yàn)中ERK蛋白在損傷組磷酸化程度明顯增加,而處理組的磷酸化程度較損傷組減輕,我們認(rèn)為,ERK/MAPK信號(hào)通路參與了雷貝拉唑?qū)Υ笫笮∧c黏膜的保護(hù)過(guò)程,可能與調(diào)節(jié)緊密連接蛋白Occludin的表達(dá)有關(guān)。

      基于以上結(jié)果,我們認(rèn)為,雷貝拉唑?qū)Υ笫驨SAIDs相關(guān)性小腸損傷具有保護(hù)作用,其可能是通過(guò)MAPK中ERK途徑,上調(diào)緊密連接蛋白Occludin的表達(dá),進(jìn)而增強(qiáng)腸上皮黏膜屏障功能而實(shí)現(xiàn)的。本實(shí)驗(yàn)僅對(duì)雷貝拉唑的腸黏膜保護(hù)作用進(jìn)行了初步探索,其他質(zhì)子泵抑制劑是否具有同樣的保護(hù)作用和機(jī)制,仍需后續(xù)研究進(jìn)一步證實(shí)。

      [1] Adebayo D, Bjarnason I. Is non-steroidal anti-inflammaory drug(NSAID)enteropathy clinically more important than NSAID gastropathy?[J].Postgrad Med J,2006,82(965):186-191

      [2] Kedika RR,Souza RF,Spechler SJ.Potential anti-inflammatory effects of proton pump inhibitors:a review and discussion of the clinical implications[J].Dig Dis Sci,2009,54(11):2312-2317.

      [3] Genta RM,Rindi G,F(xiàn)iocca R,et al.Effects of 6-12 months of esomeprazole treatment on the gastric mucosa [J].Am J Gastroenterol,2003,98(6):1257-1265.

      [4] Stupnicki T,Dietrich K,González-Carro P,et al.Efficacy and tolerability of pantoprazole compared with misoprostol for the prevention of NSAID-related gastrointestinal lesions and symptoms in rheumatic patients[J].Digestion,2003,68(4):198-208.

      [5] Laheij RJ,Van Rossum LG,Jansen JB,et al.Proton-pump inhibitor therapy for acetylsalicylic acid associated upper gastrointestinal symptoms:a randomized placebo-controlled trial[J].Aliment Pharmacol T-her,2003,18(1):109-115.

      [6] Yoda Y,Amagase K,Kato S,et al.Prevention by lansoprazole,a proton pump inhibitor,of indomethacin-induced small intestinal ulceration in rats through induction of heme oxygenase-1[J].J Physiol Pharmaeol,2010,61(3):287-294.

      [7] Pozzoli C,Menozzi A,Grandi D,et al.Protective effects of proton pump inhibitors against indomethacin-induced lesions in the rat small intestine [J].Naunyn Schmiedebergs Arch Pharmacol,2007,374(4):283-291.

      [8] Chen HQ,Lv B,Chen MY,et al.The study on the protection of proton pump inhibitors in diclofenac induced small intestinal injury[J].Chin J Dig,2011,31(11):750-765.

      陳漢卿,呂賓,陳鳴艷,等.質(zhì)子泵抑制劑對(duì)雙氯酚酸誘導(dǎo)小腸黏膜損傷保護(hù)機(jī)制研究[J].中華消化雜志,2011,31(11):750-756.

      [9] Goldstein JL,Eisen GM,Lewis B,et al.Investigators.Video capsule endoscopy to prospectively assess small bowel injury with celecoxib,naproxen plus omeprazole and placebo[J].Clin Gastroenterol Hepatol,2005,3(2):133-141.

      [10] Wallace JL,Syer S,Denou E,et al.Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis[J].Gastroenterology,2011,141(4):1314-1322.

      [11] Berkes J,Viswanathan VK,Savkovic SD,et al.Intestinal epithelial responses to enteric pathogens:effects on the tight junction barrier,ion transport,and inflammation [J].Gut,2003,52(3):439-451.

      [12] Mitic LL,Van Itallie CM,Anderson JM.Molecular physiology and pathophysiology of tight junctions I.Tight junction structure and function:lessons from mutant animals and proteins[J].Am J Physiol Gastrointest Liver Physiol,2000,279(2):G250-G254

      [13] Pan MR,Chang HC,Hung WC.Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases[J].Cell Signal,2008,20(6):1134-1141.

      [14] Samak G,Aggarwal S,Rao RK.ERK is involved in EGF-mediated protection of tight junctions,but not adherens junctions,in acetaldehyde-treated Caco-2 cell monolayers[J].Am J Physiol Gastrointest Liver Physiol,2011,301(1):G50-G59.

      [15] Basuroy S,Seth A,Elias B,et al.MAPK interacts with occludin and mediates EGF-induced prevention of tight junction disruption by hydrogen Peroxide[J].Bioehem J,2006,393(Pt 1):69-77.

      [16] Yang R,Harada T,Li J,et al.Bile modulates intestinal epithelial barrier function via an extracellular signal related kinase l/2 dependent mechanism[J].Intensive Care Med,2005,31(5):709-717.

      The effects and mechanism of rabeprazole on tight junction protein occludin expression in rats with non-steroid anti-inflammatory drugs(NSAIDs)induced small intestinal injury

      GAO Xin1,ZHANG Zhenyu1,WU Hailu1,HU Kewei1,JIANG Zongdan1,YANG Xiaobing2,WANG Jinsong2
      1.Department of Gastroenterology;2.Department of Pathology,Nanjing First Hospital Affiliated to Nanjing Medical University,Nanjing 210006,China

      ObjectiveTo explore the effects and mechanism of rabeprazole on tight junction protein occludin expression in rats with non-steroid anti-inflammatory drugs(NSAIDs)induced small intestinal injury.Methods36 SD rats were randomly and equally divided into control group,injury group and rabeprazole treated group.Except control group,rats of other two groups were gavaged with diclofenac 7.5 mg/(kg·d),once daily to make NSAIDs related small intestinal injury model.The treated group was gavaged with rabeprazola 15 mg/(kg·d)once daily 0.5 h before the administration of diclofenac.Continuous administration for four days and then executed,small intestinal tissues were taken and observed for gross and pathology changes.Immunohistochemistry and Western blot were used to detect the distribution and expression of intestinal epithelial tight junction protein occludin.The expression of phosphorylation-ERK(p-ERK)was determined by Western blot.ResultsCompared with injury group,the gross and tissue injury scores of rabeprazole treated group significantly decreased(P <0.05).The expression of occludin in injury group was decreased significantly compared with normal group(P <0.05),however,rabeprazole treated group decreased lightly(P <0.05).Significant activation of ERK were more obvious in injury group than that in normal group(P <0.05),but pretreatment with rabeprazole could inhibit the activation of ERK(P <0.05).ConclusionRabeprazole has a protective effect on NSAIDs induced small intestinal injury in rats,probably increasing the expression of tight junction protein occludin by acting ERK signaling pathways.

      Rabeprazole;NSAIDs related small intestinal injury;Occludin;MAPK/ERK

      R574

      A

      1006-5709(2012)08-0771-04

      2012-01-27

      10.3969/j.issn.1006-5709.2012.08.025

      高欣,在讀碩士。E-mail:gx_198824@sina.com

      張振玉,E-mail:ahwangzhibing776@163.com

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