袁芳岑 張振玉
非類固醇類抗炎藥(NSAID)在臨床上常用于解熱、鎮(zhèn)痛以及防治心腦血管疾病。隨著NSAID在臨床上應(yīng)用的日趨廣泛,其胃腸道不良反應(yīng)日益受到重視,長期以來學者們比較關(guān)注NSAID引起的胃黏膜損害,對小腸損害關(guān)注不夠。據(jù)文獻報道,在長期口服NSAID的患者中,小腸黏膜受損者高達70%以上[1-2]。NSAID 相 關(guān)性小腸損 傷 的 主要臨床表現(xiàn)包括NSAID腸病、小腸潰瘍、狹窄、穿孔和隔膜樣改變,其引起腸道黏膜損傷的機制尚不完全清楚,也尚無指南指出防治NSAID腸病的有效藥物。本文就NASID引起小腸損傷的可能機制及其防治的研究進展作一綜述。
目前備受推崇的是“三級打擊”學說:(1)NSAID作為一種脂溶性弱酸,擴散入上皮細胞轉(zhuǎn)變?yōu)殡x子形式,造成腸上皮細胞損傷,并引起氧化磷酸化解偶聯(lián),導(dǎo)致線粒體損傷;(2)線粒體損傷導(dǎo)致ATP合成減少,細胞內(nèi)能量缺失,鈣離子外流,引起鈣依賴酶、蛋白酶、核酸內(nèi)切酶和磷脂酶激活及細胞脂質(zhì)過氧化,并產(chǎn)生大量氧自由基,進一步損壞細胞膜的ATP泵,導(dǎo)致細胞間緊密連接處occl udin蛋白磷酸化,緊密連接被破壞,使得腸上皮細胞的通透性增強;ATP合成減少還改變了磷脂兩性陰離子功能及脂層動力學,使其疏水性變?yōu)橛H水性,破壞了腸黏膜的疏水保護屏障[3-5];(3)黏膜屏障受損使腸上皮細胞暴露于管腔內(nèi)容物(如膽汁、食物,細菌及某些酶類)的機會增加,從而引起腸黏膜損傷。
傳統(tǒng)的NSAID同時抑制環(huán)氧合酶-1(COX-1,要素酶)和COX-2(誘導(dǎo)酶),因此在其發(fā)揮抗炎作用的同時,也干擾了內(nèi)源性前列腺素合成,減少了腸道黏膜的血供,削弱了腸黏膜的防御機能,導(dǎo)致腸絨毛縮短、腸上皮細胞脫落,從而對腸黏膜造成損傷;前列腺素合成受阻后,脂氧化酶的代謝途徑活躍,代謝產(chǎn)物白三烯生成增多,不僅促進嗜中性粒細胞黏附分子的表達,使白細胞黏附于血管內(nèi)皮細胞上,同時也觸發(fā)嗜中性粒細胞釋放組織胺、氧自由基和蛋白酶,共同導(dǎo)致血管內(nèi)皮細胞損傷、毛細血管阻塞、血流量下降,進一步加重了腸道黏膜損傷[3,5-6]。
細胞凋亡是一種由基因控制的細胞自主、有序的死亡過程,它可以有效清除突變或衰老的細胞,是維持內(nèi)環(huán)境穩(wěn)定的重要機制之一。根據(jù)起始刺激不同,細胞凋亡可通過數(shù)條信號轉(zhuǎn)導(dǎo)通路發(fā)生。Bcl-2蛋白家族、線粒體、細胞色素C和天冬氨酸特異性半胱氨酸蛋白酶(caspase)是細胞內(nèi)凋亡信號通路的基本組分[7]。細胞凋亡從內(nèi)外多因子復(fù)雜的相互作用誘導(dǎo)產(chǎn)生凋亡信號,傳遞至caspase并使其活化開始,以蛋白裂解、細胞解體為結(jié)局,從而使細胞凋亡得以完成[8]。研究表明,NSAID可使黏膜結(jié)構(gòu)型一氧化氮合酶(c NOS)活性下降、誘導(dǎo)型一氧化氮合酶(i NOS)活性升高,并與caspases活性變化及黏膜細胞凋亡有關(guān);一氧化氮釋放型NSAID(NO-NSAID)可以抑制caspase-1、3活性,抑制細胞凋亡[9]。
有研究發(fā)現(xiàn),NSAID可激活腸黏膜中的i NOS,產(chǎn)生大量一氧化氮(NO),同時合成 O2-[10-12]。有研究發(fā)現(xiàn),NO對細胞凋亡有雙向調(diào)節(jié)作用,即生理條件下的低水平NO可以促進腸道腺體分泌,抑制細菌移位,而病理狀態(tài)下的高水平NO可導(dǎo)致某些類型的細胞凋亡;其機制可能與氧自由基氧化生成劇毒的ONOO-,ONOO-又降解為OH-和NO2-,NO、O2-、ONOO-、OH-、NO2-對腸黏膜細胞直接產(chǎn)生細胞毒作用有關(guān);此外,ONOO-是一種強氧化劑,具有強烈的抑制細胞線粒體氧化的作用,導(dǎo)致能量代謝障礙,細胞脂質(zhì)過氧化損傷,最終引起腸黏膜損傷[13-16]。過量表達的NO還可誘導(dǎo)鈣離子通道開放,使細胞外鈣離子大量內(nèi)流,從而觸發(fā)還原型煙酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶,產(chǎn)生大量氧自由基,加劇了黏膜細胞死亡[17]。
正常狀態(tài)下,小腸上皮細胞處于弱堿性環(huán)境中,NSAID可直接刺激小腸黏膜,引起細胞膜通透性增加,使腸內(nèi)細菌易于侵襲;細菌侵入以及膽汁、脂肪酶/胰腺分泌物等化學刺激又可引起小腸上皮細胞的炎性反應(yīng)[18]。NSAID吸收后進入腸肝循環(huán),與膽鹽競爭性結(jié)合卵磷脂,使膽鹽成為游離狀態(tài),游離的膽鹽對腸黏膜細胞具有直接的細胞毒作用,使腸道黏膜受損。膽汁與NSAID結(jié)合的復(fù)合物對小腸黏膜的損傷作用大于單一的NSAID,同時腸肝循環(huán)延長了NSAID與小腸壁的接觸時間,加重了小腸損傷[18-19]。
目前用于防治NSAID相關(guān)性胃黏膜損傷的藥物有許多種,但對NSAID所致小腸黏膜損傷至今仍缺乏有效防治措施。防治NSAID所致小腸黏膜損傷的藥物包括黏膜保護劑、抑酸藥物、抗菌藥物、益生菌制劑、生物制劑,還有食物等其他防治措施。
早在1989年Bjar nason等[20]就發(fā)現(xiàn),米索前列醇能夠減少吲哚美辛引起的小腸病變的概率和嚴重程度。Mohajer等[21]認為,其保護機制包括促進小腸分泌、增強黏膜保護、增強上皮及內(nèi)皮細胞屏障功能及促進腸動力等。Diao等[22]測定了大鼠腸黏膜的通透性,發(fā)現(xiàn)瑞巴派特通過線粒體降低雙氯芬酸腸損傷的黏膜通透性,從而保護了小腸黏膜。Satoh等[23]的 Wistar大鼠實驗發(fā)現(xiàn),黏膜保護藥(米索前列醇、瑞巴派特、伊索拉定)通過抑制黏液減少起到對NSAID損傷腸黏膜的保護作用。Shibamori等[24]則認為,瑞巴派特調(diào)整了腸道菌群,同時抑制了COX-2和腫瘤壞死因子-α(TNF-α),從而對小腸損傷起到保護作用。
Wallace等[25]認為質(zhì)子泵抑制劑(PPI)能夠通過抑制菌群移位來防止NSAID所致小腸損傷。Umegaki等[26]觀察口服2周雙氯芬酸的志愿者分別用替普瑞酮和法莫替丁干預(yù)后的效果,結(jié)果發(fā)現(xiàn)與法莫替丁相比,替普瑞酮顯著抑制了小腸病變的發(fā)展,而上消化道的這種差異不明顯。Kuramoto等[27]研究發(fā)現(xiàn),伊索拉定能夠抑制NSAID腸病。Satoh等[28]的一系列臨床試驗顯示,蘭索拉唑有保護NSAID小腸損傷的作用,而雷貝拉唑、奧美拉唑及H2受體拮抗劑(H2-RA)反而會加重NSAID所致小腸損傷。
Packey等[29]認為鹽酸阿霉素改變了空腸和遠端回腸的對比微生物反應(yīng),因此對NASID腸病有抑制作用;Saitta等[30]研究發(fā)現(xiàn),細菌β-葡萄糖醛酸酶可以保護吲哚美辛、酮洛芬、雙氯芬酸引起的小鼠腸黏膜損傷。Leite等[31]早在2001年就發(fā)現(xiàn)甲硝唑可以保護NSAID腸損傷,其機制可能與線粒體氧化磷酸化解偶聯(lián)有關(guān)。Watanabe等[32]的大鼠實驗發(fā)現(xiàn),干酪乳桿菌對吲哚美辛引起的腸損傷有預(yù)防作用,認為是通過左旋乳酸抑制了脂多糖/Toll樣受體4(LPS/TLR4)信號通路而發(fā)揮作用的。Montalto等[33]進行了一項隨機雙盲試驗,給予20名志愿者服用21 d益生菌合劑(VSL#3)或安慰劑,從第16天開始給予志愿者口服吲哚美辛(50 mg/d),并從第15天開始測定糞鈣衛(wèi)蛋白(腸道炎性反應(yīng)標志物),結(jié)果顯示預(yù)先服用VSL#3可以抑制糞鈣衛(wèi)蛋白表達升高,減輕腸道炎性反應(yīng),保護腸道黏膜。
Mencarelli等[34]研究發(fā)現(xiàn),抗人類免疫缺陷病毒(HIV)蛋白酶抑制劑與NSAID作用可降低NSAID腸病的發(fā)生率。Theiss等[35]研究發(fā)現(xiàn),抗增殖蛋白(PHB)能夠?qū)鼓c黏膜的氧化應(yīng)激反應(yīng),從而對NSAID小腸病變起到保護作用。Reuter等[36]研究發(fā)現(xiàn),磷酸二酯酶抑制劑可能能夠預(yù)防NSAID腸病,其機制應(yīng)與抑制TNF-α合成相關(guān)。多巴胺D2受體(D2 R)拮抗劑嗎叮啉是被熟知的胃腸促動力藥,Kawahara等[37]研究發(fā)現(xiàn),嗎叮啉通過激活α7乙酰膽堿受體,能夠?qū)SAID小腸潰瘍起到保護作用。Cipriani等[38]研究發(fā)現(xiàn),G蛋白偶聯(lián)膽汁酸受體1(GPBAR1)對維持胃腸黏膜的完整性起著重要的作用,缺乏這種受體的小鼠腸黏膜對甲氧萘丙酸(消痛靈)更敏感,更容易受到損傷,而GPBAR1激動劑對阿司匹林和NSAID引起的胃腸黏膜損傷起到保護作用,其機制可能為COX非依賴性。Halista等[39]研究證實,熊去氧膽酸確實能抵御NSAID引起的腸黏膜損害。Inoue等[40]研究發(fā)現(xiàn),二肽基肽酶-Ⅳ(DPP-Ⅳ)能夠預(yù)防大鼠在吲哚美辛灌胃后發(fā)生NASID腸損傷,并對潰瘍恢復(fù)有促進作用。
近年來蘿卜硫素被證實通過激活nrf2-keap1途徑依賴的抗氧化系統(tǒng)以及抑制厭氧菌侵襲腸黏膜來防止 NSAID 小腸損傷[41-42]。Satoh等[43]比較了喂食普通飼料和含可溶性纖維素食物的貓的小腸黏液素改變,發(fā)現(xiàn)可溶性纖維素可能通過改善黏液素屏障來預(yù)防 NSAID腸損傷。Carrasco-Pozo等[44]的大鼠實驗發(fā)現(xiàn),蘋果皮多酚也有預(yù)防NSAID腸損傷的作用。Amagase等[45]研究認為,谷氨酸鹽可減少大鼠NSAID腸損傷的發(fā)生率。
Sivalingam等[46]認為鋅可以有效保護吲哚美辛引起的小腸損傷,其機制可能與金屬硫蛋白誘發(fā)有關(guān)。熱休克蛋白(HSP)近年來被證實在細胞生長調(diào)控和凋亡中發(fā)揮了重要的作用。Tamaki等[47]的實驗發(fā)現(xiàn),經(jīng)中藥六君子湯(TJ-43)預(yù)處理過的IEC-6細胞HSP60蛋白表達升高,細胞壞死和凋亡率明顯下降。Yoriki等[48]先用吲哚美辛制備NSAID腸病模型小鼠,實驗組用氯化血紅素預(yù)處理,結(jié)果發(fā)現(xiàn)實驗組小鼠血紅素氧化酶-1(HO-1)被激活,潰瘍病變的嚴重程度及數(shù)量、髓過氧化物酶活性、炎性細胞因子及趨化因子的mRNA表達均下降,若加用HO-1特異性抑制劑鋅原卟啉(Zn PP)則其保護作用將失效。Mei等[49]研究發(fā)現(xiàn),與對照組相比,雙氯芬酸誘導(dǎo)的小腸損傷大鼠的腸黏膜通透性增加,潰瘍數(shù)目更多,病變程度更嚴重,病理評分更高,丙二醛(MDA)、髓過氧化物酶(MPO)活性也更高;經(jīng)褪黑素處理的大鼠的上述指標均好于雙氯芬酸組,在透射電鏡下可見其小腸絨毛形態(tài)和細胞間隙與對照組相似,ATP酶及琥珀酸脫氫酶(SDH)的活性也明顯恢復(fù)了。Chao等[50]研究發(fā)現(xiàn),用云母預(yù)處理后,雙氯芬酸誘導(dǎo)的NSAID腸病大鼠的小腸黏膜損傷明顯減輕,其機制可能與增強黏膜屏障功能、增加表皮生長因子(EGF)表達相關(guān)。
目前研究報道的治療藥物種類繁多,但大多為動物實驗,存在一定局限性,是否適用于人體亟需進一步證實,其有效性及安全性也有待多中心臨床試驗數(shù)據(jù)證實。日本的一項多中心隨機雙盲對照臨床試驗證實,瑞巴派特對小劑量阿司匹林/NSAID引起的小腸病變有治療作用[51],這無疑是廣大NSAID腸病患者的福音,但NSAID致小腸黏膜損傷的機制及瑞巴派特保護NSAID腸病的機制尚未明確,有待進一步研究。
1 Bjarnason I,Macpherson A,Hollander D.Intestinal per meability:an overview.Gastr oenter ology,1995,108:1566-1581.
2 Tibble JA,Sigt horsson G,F(xiàn)oster R,et al.High prevalence of NSAID enteropat hy as shown by a si mple faecal test.Gut,1999,45:362-366.
3 安敏,張振玉,安敏.非甾體類抗炎藥相關(guān)性腸病.世界華人消化雜志,2009,17:174-180.
4 Higuchi K,Umegaki E,Watanabe T,et al.Present status and strategy of NSAIDs-induced small bowel injury. J Gastr oenterol,2009,44:879-888.
5 羅佳,王惠吉,郝瑞瑞.非甾體抗炎藥所致腸道損傷.中國藥物警戒,2011,8:302-305.
6 張振玉.非甾體抗炎藥誘發(fā)腸病的診治.臨床藥物治療雜志,2010,8:54-55.
7 崔忠敏.細胞凋亡在非甾體類抗炎藥物所致胃黏膜損傷中的作用及機制研究.上海:第二軍醫(yī)大學,2000.
8 廖永暉,湯雨,千年松,等.氧化應(yīng)激與細胞凋亡.新鄉(xiāng)醫(yī)學院學報,2011,28:110-113.
9 易鐵男.Caspase家族與細胞凋亡的研究進展.國外醫(yī)學:腫瘤學分冊,2001,28:39-42.
10 Bjar nason I,Hayllar J,Smet hurst P,et al.Metr onidazole reduces intestinal inflammation and blood loss in non-steroidal anti-infla mmatory dr ug induced enter opat hy.Gut,1992,33:1204-1208.
11 Lisotti A,Grenci C,Caponi A,et al.The management of NSAIDs t herapy:how t o mini mize upper gastrointestinal tract damage.Minerva Gastroenter ol Diet ol,2008,54:323-329.
12 韓偉,韓英.非甾體類抗炎藥與胃腸道損傷.世界華人消化雜志,1998,6:351-351.
13 Hsu DZ,Liu MY.Involve ment of nitric oxide in gastric protection of epinephrine in endotoxin intoxication in rats.Toxicology,2004,204:203-208.
14 W hittle BJ.Gastr ointestinal eff ects of nonst er oidal antiinflammatory drugs.Fundam Clin Phar macol,2003,17:301-313.
15 Lipton SA,Choi YB,Pan ZH,et al.A redox-based mechanis m f or the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-co mpounds. Nat ure,1993,364:626-632.
16 施華秀,任建林.氧自由基與胃黏膜損傷.世界華人消化雜志,2005,13:2582-2585.
17 Yanaka K,Ca marata PJ,Spell man SR,et al.Antagonis m of leukocyte adherence by synthetic fibronectin peptide V in a rat model of transient f ocal cerebral ischemia.Neurosurger y,1997,40:557-564.
18 欒好波.非甾體類抗炎藥物對胃腸道損傷機制及預(yù)防.齊魯藥事,2007,26:297-299.
19 Barrios JM,Lichtenber ger L M.Role of biliar y phosphatidylcholine in bile acid protection and NSAID injury of the ileal mucosa in rats.Gastroenter ology,2000,118:1179-1186.
20 Bjar nason I,Smet hurst P,F(xiàn)enn CG,et al.Misopr ost ol reduces indomethacin-induced changes in hu man small intestinal per meability.Dig Dis Sci,1989,34:407-411.
21 Mohajer B,Ma T Y.Eicosanoids and t he s mall intestine.Prostaglandins Other Lipid Mediat,2000,61:125-143.
22 Diao L,Mei Q,Xu J M,et al.Reba mipide suppr esses diclofenac-induced intestinal per meability via mitochondrial protection in mice. World J Gastroenterol,2012,18:1059-1066.
23 Satoh H,Amagase K,Takeuchi K.Mucosal protective agents prevent exacerbation of NSAID-induced small intestinal lesions caused by antisecretor y dr ugs in rats.J Phar macol Exp Ther,2014,348:227-235.
24 Shiba mori M,Ue matsu N,Nakashi ma T,et al.Mo2052 pr otective effects of rebamipide on indo met hacin-induced small intestinal injur y mediated by modulation of intestinal flora and inhibition of dual oxidase2 and TNF-α.Gastr oenterology,2012,142(Suppl 1):S729.
25 Wallace JL,Syer S,Denou E,et al.Proton pu mp inhibitors exacer bate NSAID-induced s mall intestinal injur y by inducing dysbiosis.Gastroenterology,2011,141:1314-1322.
26 Umegaki E,Kura moto T,Koji ma Y,et al.Geranylgeranylacetone,a gastro mucopr otective dr ug, pr otects against NSAID-induced esophageal,gastroduodenal and small intestinal mucosal injur y in healt hy subjects:a prospective rando mized st udy involving a co mparison wit h fa motidine.Inter n Med,2014,53:283-290.
27 K ur a m ot o T,U m egaki E,K oji m a Y,et al.T u1 5 5 3 irsogladine,a gastr opr otective dr ug,pr otects against NSAID-induced esophagitis,peptic ulcers,and s mall intestinal mucosal damages in healthy subjects:a prospective randomised study of co mparison wit h o meprazole. Gastr ointest Endosc,2011,73:AB445.
28 Sat oh H,A m agase K,T akeuchi K.Exacer bation of nonsteroidal anti-infla mmatory dr ug-induced s mall intestinal lesions by antisecretory dr ugs in rats:t he r ole of intestinal motility.J Phar macol Exp Ther,2012,343:270-277.
29 Packey CD,Ge wain K,Sart or RB,et al.Tu2 0 2 7 t he chemot herapeutic agent doxor ubicin induces contrasting microbial responses in the jejunu m and distal ileu m that may contribute to differential injury patter ns.Gastr oenter ology,2013,144(Suppl 1):S907-S908.
30 Saitta KS,Zhang C,Lee KK,et al.Bacterialβ-glucuronidase inhibition pr otects mice against enter opat hy induced by indo met hacin,ketoprofen or diclofenac:mode of action and phar macokinetics.Xenobiotica,2013,44:28-35.
31 Leite AZ,Sipahi A M,Da mi?o AO,et al.Protective effect of metronidazole on uncoupling mitochondrial oxidative phosphorylation induced by NSAID:a new mechanism.Gut,2001,48:163-167.
32 W at anabe T,Nishio H,Taniga wa T,et al.Pr obiotic Lactobacill us casei strain Shirota prevents indomethacin-induced s mall intestinal injury:involvement of lactic acid.Am J Physiol Gastr ointest Liver Physiol,2009,297:506-513.
33 Montalto M,Gallo A,Curigliano V,et al.Clinical trial:the effects of a pr obiotic mixt ure on non-ster oidal anti-infla mmatory dr ug enteropat hy--a rando mized, double-blind,cr oss-over,placebo-controlled study.Ali ment Phar macol Ther,2010,32:209-214.
34 Mencarelli A,Cipriani S,Distr utti E,et al.Anti-HIV protease inhibitors interact with NSAIDs and exacerbate small intestine enteropat hy induced by NSAIDs.Gastr oenter ology,2011,140(Suppl 1):S652.
35 Theiss AL,Idell RD,Srinivasan S,et al.Prohibitin protects against oxidative stress in intestinal epit helial cells.FASEB J,2007,21:197-206.
36 Reuter BK,Wallace JL.Phosphodiesterase inhibitors prevent NSAID enteropat hy independently of effects on TNF-αrelease.Am J Physiol Gastr ointest Liver Physiol,1999,277:847-854.
37 Kawahara R,Hashi mura H,Yasuda M,et al.Protective effect of do mperidone,a dopamine D2 receptor antagonist,on indo met hacin-induced s mall intestinal ulceration in mice t hr ough activation of α7 nicotinic acet ylcholine recept ors.Gastr oenter ology,2011,140(Suppl 1):S652.
38 Cipriani S,Mencarelli A,Br uno A,et al.Activation of t he bile acid receptor GPBAR1 protects against gastrointestinal injury caused by non-ster oidal anti-inflammatory dr ugs and aspirin in mice.Br J Phar macol,2013,168:225-237.
39 Halista M,Dial E,Lichtenberger L M.Su1762 ursodeoxycholic acid (URSO) may be protective against NSAID-induced intestinal injur y. Gastr oenterology, 2012, 142 (Suppl 1):S497.
40 Inoue T,Akiba Y,Engel E,et al.Dipeptidyl peptidaseⅣinhibit or prevents and pro motes healing of indo met hacin-induced intestinal mucosal injur y in rats.Gastr oenter ology,2011,140(Suppl 1):S654.
41 Yanaka A,Sato J,Oh mori S.Sulf oraphane protects s mall intestinal mucosa fro m aspirin/NSAID-induced injur y by enhancing host defense systems against oxidative stress and by inhibiting mucosal invasion of anaerobic enter obacteria.Curr Phar m Des,2013,19:157-162.
42 Oh mori S,F(xiàn)uku moto A,Sato J,et al.Sulf oraphane and rebarnipide protect s mall intestinal mucosa fro m indo met hacininduced injury t hrough different mechanis ms in mice in vivo.Gastroenterology,2011,140(Suppl 1):S655.
43 Sat oh H,Hara T,Murakawa D,et al.Soluble dietary fiber pr otects against nonster oidal anti-infla mmat ory dr ug-induced damage to the small intestine in cats.Dig Dis Sci,2010,55:1264-1271.
44 Carrasco-Pozo C,Speisky H,Br unser O,et al.Apple peel polyphenols protect against gastrointestinal mucosa alterations induced by indo met hacin in rats.J Agric Food Chem,2011,59:6459-6466.
45 Amagase K,Nakamura E,Kato S,et al.Prophylactic effect of gluta mate on gastr ointestinal damage.Yakugaku Zasshi,2011,131:1711-1719.
46 Sivalingam N,Pichandi S,Chapla A,et al.Zinc protects against indo met hacin-induced da mage in t he rat s mall intestin.Eur J Phar macol,2011,654:106-116.
47 Ta maki K,Otaka M,Shibuya T,et al.Traditional herbal medicine, rikkunshit o, induces HSP60 and enhances cytopr otection of s mall intestinal mucosal cells as a nontoxic chaperone inducer.Evid Based Complement Alternat Med,2012,2012:278958.
48 Yoriki H,Nait o Y,Takagi T,et al.He min a meliorates indomethacin-induced small intestinal injury in mice through the induction of he me oxygenase-1.J Gastr oenterol Hepatol,2013,28:632-638.
49 Mei Q,Diao L,Xu JM,et al.A protective effect of melatonin on intestinal per meability is induced by diclofenac via regulation of mitochondrial f unction in mice.Acta phar macol Sin,2011,32:495-502.
50 Chao G,Zhang S.Therapeutic effects of muscovite to nonster oidal anti-infla mmat ory dr ugs-induced s mall intestinal disease.Int J Phar m,2012,436:154-160.
51 Kur okawa S,Katsuki S,F(xiàn)ujita T,et al.A rando mized,double-blinded,placebo-controlled,multicenter trial,healing effect of reba mipide in patients with low-dose aspirin and/or non-ster oidal anti-infla mmat ory dr ug induced s mall bowel injur y.J Gastr oenterol,2014:239-244.