膽汁淤積性肝病由肝細(xì)胞和膽管上皮細(xì)胞損傷及膽管梗阻導(dǎo)致。膽汁淤積時,細(xì)胞外基質(zhì)合成增加且廣泛沉積在肝竇周間隙,肝內(nèi)膠原纖維異常增生而導(dǎo)致肝纖維化,甚至發(fā)展為肝硬化。肝纖維化及肝硬化患者常合并腸道屏障功能障礙,腸道通透性改變;同時腸道微生態(tài)改變、細(xì)菌和內(nèi)毒素經(jīng)門靜脈入血,繼而激活全身炎癥反應(yīng),引起多個器官功能障礙。內(nèi)毒素誘導(dǎo)的全身炎性細(xì)胞因子增加和氧化應(yīng)激又加重腸道和肝損傷,進(jìn)一步促進(jìn)細(xì)菌移位和內(nèi)毒素血癥。因此保護(hù)腸屏障對于阻止肝病進(jìn)展及預(yù)防并發(fā)癥至關(guān)重要。膽汁淤積性肝纖維化時,腸道膽汁酸缺如或減少可導(dǎo)致細(xì)菌在腸道內(nèi)過度生長和菌群結(jié)構(gòu)改變。一些致病性、促炎性微生物,如:紫單胞菌科和腸桿菌科過度生長,腸道通透性增加,脂多糖（lipopolysaccharide,LPS）和細(xì)菌移位引起炎癥反應(yīng),進(jìn)一步加重腸屏障損害。腸黏膜屏障作為保護(hù)機體的第一道防線,可以抵抗腸腔中細(xì)菌、食物抗原、毒素等外源性物質(zhì)的損傷,其中以機械屏障最為重要,其結(jié)構(gòu)基礎(chǔ)為完整的腸上皮細(xì)胞及之間的緊密連接（tight junction,TJ）。血紅素在血紅素氧合酶-1（Heme Oxygenase-1,HO-1）的作用下可生... 

【文章來源】：大連醫(yī)科大學(xué)遼寧省

【文章頁數(shù)】：128 頁

【學(xué)位級別】：博士

【部分圖文】：

Caco-2細(xì)胞模型培養(yǎng)示意圖

Caco-2 細(xì)胞單層模型 A：形態(tài)學(xué)表現(xiàn)：鏡下觀察 Caco-2 細(xì)胞生長形成完整致密的細(xì)胞（×100）；B：TEER 檢測結(jié)果。同濃度 LPS 對 Caco-2 單層細(xì)胞 TEER 及緊密連接蛋白的影響在本實驗中，我們分別檢測了不同濃度的 LPS 對 Caco-2 單層細(xì)胞 TEER 的作同時觀察了不同濃度 LPS 對腸上皮緊密連接蛋白（ZO-1、occludin 及 claudinmRNA 及蛋白的影響。結(jié)果顯示和對照組相比，100μg/ml 及 10μg/ml 的 LPS后可以顯著降低 Caco-2 單層細(xì)胞 TEER 值（圖 3A）。同時 qPCR 及 Western blot

圖 3 LPS 刺激對 Caco-2 單層細(xì)胞 TEER 及緊密連接蛋白的影響。A：TEER 變化；B：不同濃度 LPS 刺激對 claudin-1、occludin 和 ZO-1 mRNA 表達(dá)的影響；C：Western blot 方法檢測claudin-1、occludin 和 ZO-1 表達(dá)；D：經(jīng)β-actin 標(biāo)化后，緊密連接蛋白的相對表達(dá)量。與對

【參考文獻(xiàn)】：
期刊論文
[1]Fatty liver diseases,bile acids,and FXR[J]. Yan Zhu,Hongxia Liu,Min Zhang,Grace L.Guo.  Acta Pharmaceutica Sinica B. 2016(05)
[2]Intestinal barrier dysfunction in cirrhosis: Current concepts in pathophysiology and clinical implications[J]. Georgios I Tsiaoussis,Stelios F Assimakopoulos,Athanassios C Tsamandas,Christos K Triantos,Konstantinos C Thomopoulos.  World Journal of Hepatology. 2015(17)
[3]Microbiota and the gut-liver axis:Bacterial translocation,inflammation and infection in cirrhosis[J]. Valerio Giannelli,Vincenza Di Gregorio,Valerio Iebba,Michela Giusto,Serena Schippa,Manuela Merli,Ulrich Thalheimer.  World Journal of Gastroenterology. 2014(45)
[4]Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury[J]. Clarice Silvia Taemi Origassa,Niels Olsen Saraiva Cmara.  World Journal of Hepatology. 2013(10)
[5]Effects of Lactobacillus plantarum on gut barrier function in experimental obstructive jaundice[J]. Yu-Kun Zhou,Department of Hepatobiliary Surgery,No.455 Hospital of People’s Liberation Army,Shanghai 200052,China Huan-Long Qin,Ming Zhang,Tong-Yi Shen,Hong-Qi Chen,Yan-Lei Ma,Zhao-Xin Chu,Peng Zhang,Zhi-Hua Liu,Department of Surgery,The Sixth People’s Hospital,Shanghai Jiaotong University,Shanghai 200233,China.  World Journal of Gastroenterology. 2012(30)
[6]Enterocytes’tight junctions:From molecules to diseases[J]. Stelios F Assimakopoulos,Ismini Papageorgiou,Aristidis Charonis.  World Journal of Gastrointestinal Pathophysiology. 2011(06)
[7]Non-invasive assessment of barrier integrity and function of the human gut[J]. Joep Grootjans,Geertje Thuijls,Froukje Verdam,Joep PM Derikx,Kaatje Lenaerts,Wim A Buurman.  World Journal of Gastrointestinal Surgery. 2010(03)
[8]Clinical value of fecal calprotectin in determining disease activity of ulcerative colitis[J]. Jun-Ying Xiang, Qin Ouyang, Guo-Dong Li, Nan-Ping Xiao, Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.  World Journal of Gastroenterology. 2008(01)



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