發(fā)布時間：2018-03-05 16:01

  本文選題：肝纖維化　切入點：白介素-22　出處：《廣西醫(yī)科大學》2017年博士論文　論文類型：學位論文

【摘要】：肝纖維化是各種慢性肝病向肝硬化發(fā)展所共有的病理改變和必經(jīng)途徑,以細胞外基質異常增生和在肝內過量沉積為病理特征。肝星狀細胞(Hepatic stellate cells,HSCs)的異常激活和分泌致纖維化因子是肝纖維化發(fā)生的重要原因。研究表明,多種細胞因子和mi RNAs在肝纖維化的發(fā)生和發(fā)展過程中扮演著重要角色?IL-22可由多種免疫細胞分泌,通過與細胞表面的IL-22受體結合后,激活細胞內信號傳導與轉錄激活因子(signal transducer and activator of transcription,STAT)發(fā)揮調控作用。mi RNAs通過與靶m RNA完全或不完全配對形成沉默復合體,在轉錄后水平對基因轉錄進行負調控。mi R-200a在肝纖維化患者和大小鼠肝纖維模型中均表達下調,并通過抑制靶基因發(fā)揮抑制HSCs活性的作用。我們前期研究已發(fā)現(xiàn)IL-22可以抑制HSCs活性和發(fā)揮抗小鼠肝纖維化作用,但IL-22是否與mi R-200a有交互作用關系?如果有,相關細胞因子變化及其相互關系如何?目前無相關研究?為進一步了解IL-22和mi R-200a在抗肝纖維化作用的機制,并闡明IL-22和mi R-200a在肝纖維化中的交互作用(cross-talk)關系,進而探索出肝纖維化新的治療靶點,本研究應用大鼠HSCs和肝纖維化模型,分別給予IL-22和mi R-200a干預,檢測相關下游因子的改變情況,觀察兩者在HSCs和肝纖維化模型中的交互作用。本研究將從以下三方面進行研究:第一部分IL-22經(jīng)STAT3通路抑制HSCs活性和抗肝纖維作用研究目的:觀察IL-22干預HSCs后,細胞活性的改變情況,并觀察IL-22對大鼠肝纖維化模型的作用,探討IL-22抑制HSCs活性和抗肝纖維作用的機制。方法:培養(yǎng)大鼠HSCs細胞系(HSCs-T6)至對數(shù)生長期,分別使用250pg/mL、500pg/m L、750pg/m L和1000pg/m L濃度的IL-22加入培養(yǎng)基中干預48小時;分別采用0、2、5ng/m L濃度的TGF-β1加入培養(yǎng)基24小時激活HSCs;CCK8法檢測細胞增殖率,流式細胞術檢測細胞凋亡率,ELISA檢測細胞培養(yǎng)上清液中的α-平滑肌肌動蛋白(α-smooth muscle actin,α-SMA)和膠原蛋白I(Col I)表達水平,western-blot法檢測細胞中的STAT3和p-STAT3蛋白表達水平;采用CCL4腹腔注射大鼠8周構建大鼠肝纖維化模型,在給予IL-22腹腔注射1周,處死大鼠,收集肝臟組織,HE和Masson染色觀察小鼠肝臟病理改變,根據(jù)Ishak評分系統(tǒng)評估肝纖維化的程度;免疫組織化學染色檢測肝臟組織中α-SMA,western-blot法檢測肝組中的STAT3和p-STAT3蛋白表達水平。結果:隨著IL-22濃度的升高,HSCs增殖率下降,到750 pg/m L時,與無IL-22干預相比差異有統(tǒng)計學意義(P0.05)。但隨著IL-22濃度的升高,HSCs凋亡率無顯著改變。ELIAS法檢測培養(yǎng)上清液中的α-SMA和Col I隨著IL-22濃度的升高而下降,到750pg/m L時,α-SMA水平與無IL-22干預相比差異有統(tǒng)計學意義(P0.05);隨著TGF-β1濃度的升高,HSCs增殖率上升,到5 ng/m L時,HSCs的增殖率與無TGF-β1干預相比差異有統(tǒng)計學意義(P0.05)。STAT3蛋白表達水平隨著TGF-β1濃度的升高無顯著改變,而p-STAT3蛋白表達水平隨著TGF-β1濃度的升高而下降,到5ng/m L時,p-STAT3蛋白表達水平比無TGF-β1干預時顯著下降,差異有統(tǒng)計學意義(P0.05);采用TGF-β1預處理HSCs,再使用IL-22分別干預后,STAT3蛋白表達水平無顯著改變,而p-STAT3蛋白表達水平顯著上升(P0.05);大鼠模型實驗中,與未進行IL-22干預相比,IL-22干預后,大鼠肝纖維化明顯改善,肝臟Ishak組織學評分顯示差異有統(tǒng)計學意義(P0.05),肝組織中的STAT3蛋白表達水平無顯著改變,而p-STAT3蛋白表達水平顯著上升(P0.05)。結論:IL-22以濃度依賴性抑制HSCs增殖和活性,但對HSCs凋亡無顯著影響;IL-22可以有效的抑制HSCs活性和抗肝纖維化作用,其機制是通過激活STAT3磷酸化信號通路表達實現(xiàn)的。第二部分miR-200a靶向β-catenin抑制HSCs增殖與活性目的:檢測miR-200a在HSCs和肝纖維化組織的表達情況,并觀察過表達miR-200a對HSCs的影響;驗證miR-200a對β-catenin直接調控作用,并在HSCs驗證,闡明miR-200a靶向β-catenin抑制HSCs增殖與活性的機制。方法:培養(yǎng)HSCs至對數(shù)培養(yǎng)期,分別采用0、5ng/m L濃度的TGF-β1加入培養(yǎng)基中干預24小時,采用熒光定量PCR法檢測HSCs中的miR-200a表達情況;采用慢病毒包裝的miR-200a mimics轉染HSCs,觀察過表達HSCs中的miR-200a對HSCs的影響;CCK8法檢測細胞增殖率,流式細胞術檢測細胞凋亡率,ELISA檢測細胞培養(yǎng)上清液中的α-SMA表達水平,western-blot法檢測細胞中的β-catenin蛋白表達水平。使用在線數(shù)據(jù)庫Targetscan預測miR-200a的靶基因,在使用雙熒光素酶報告系統(tǒng)驗證miR-200a對β-catenin直接調控作用,結果:TGF-β1激活后,HSCs中的miR-200a表達水平顯著下降,與無TGF-β1激活相比差異有統(tǒng)計學意義(P0.05)。使用慢病毒包裝的大鼠miR-200a mimics培養(yǎng)基轉染HSCs,與未進行miR-200a轉染的HSCs相比,轉染了miR-200a的HSCs中,miR-200a表達升高打8倍以上;CCK8法發(fā)現(xiàn)HSCs增殖率下降,與未進行miR-200a mimics相比差異有統(tǒng)計學意義(P0.05)。ELIAS法發(fā)現(xiàn)miR-200a mimics轉染后,HSCs培養(yǎng)上清液中的α-SMA水平下降,與未進行miR-200amimics相比差異有統(tǒng)計學意義(P0.05)。雙熒光素酶系統(tǒng)顯示轉染了miR-200a mimics和β-catenin質粒后,細胞中的熒光素酶活性顯著下降(P0.05);western-blot法顯示HSCs轉染miR-200a mimics后,細胞中的β-catenin蛋白表達水平下降(P0.05)。結論:miR-200a在HSCs激活過程中表達下降,過表達miR-200a可以抑制HSCs增殖和活性;雙熒光素酶系統(tǒng)驗證了β-catenin是miR-200a的直接靶基因;miR-200a通過靶向調控β-catenin抑制HSCs增殖和活性。第三部分IL-22與miR-200a在HSCs和肝纖維組織中交互作用研究目的:觀察IL-22干預HSCs和大鼠肝纖維化模型以及抑制miR-200a后,HSCs和肝纖維化組織中的IL-22和miR-200a下游因子的表達情況,闡明IL-22與miR-200a在HSCs和肝纖維組織中交互作用機制。方法:IL-22干預HSCs后細胞,熒光定量PCR和western-blot分別檢測細胞中miR-200a和β-catenin表達的情況;慢病毒轉染miR-200a inhibitors至HSCs,抑制HSCs中的miR-200a表達,再給予IL-22干預,觀察抑制miR-200a后,IL-22對HSCs的影響,ELISA檢測細胞培養(yǎng)上清液中的α-SMA表達水平;western-blot法檢測細胞中的STAT3和p-STAT3蛋白表達水平。采用CCL4腹腔注射大鼠4周構建大鼠肝纖維化模型,在給予IL-22腹腔注射,同時給予尾靜脈注射慢病毒包裝的miR-200a inhibitors,1周后處死大鼠,收集肝臟組織,抑制大鼠肝纖維化模型中的miR-200a,HE和Masson染色觀察小鼠肝臟病理改變并根據(jù)Ishak評分系統(tǒng)評估肝纖維化的程度;免疫組織化學染色檢測肝臟組織中α-SMA,western-blot法檢測肝組中的β-catenin、STAT3和p-STAT3蛋白表達水平,觀察抑制miR-200a后,IL-22對大鼠肝纖維化的影響;結果:TGF-β1加入培養(yǎng)基中激活HSCs活性,在給予IL-22干預,發(fā)現(xiàn)與未進行IL-22干預相比,IL-22干預后HSCs中的miR-200a水平上升,而β-catenin蛋白水平下降;轉染了miR-200a inhibitors的HSCs中β-catenin蛋白表達水平顯著升高(P0.05),STAT3蛋白表達水平無顯著改變,但p-STAT3的蛋白表達水平明顯下降(P0.05);大鼠肝纖維化模型構建成功后,分為IL-22和miR-200a inhibitors單獨注射組和IL-22+miR-200a inhibitors注射組,轉染了miR-200a inhibitors的肝組織中的miR-200a表達比未轉染miR-200a inhibitors的低,IL-22的抗肝纖維化作用被miR-200a inhibitors抑制,而β-catenin蛋白表達水平也較升高(P0.05),STAT3蛋白表達水平無顯著改變,但p-STAT3的蛋白表達水平明顯下降(P0.05)。結論:IL-22可以上調HSCs中的miR-200a表達量,進而下調β-catenin表達水平;抑制miR-200a表達量可以抑制IL-22對HSCs的作用,并抑制STAT3磷酸化水平;IL-22改善大鼠肝纖維化作用可被miR-200a inhibitors抑制,STAT3磷酸化水平也被抑制。
[Abstract]:Hepatic fibrosis is a chronic liver disease to liver cirrhosis is the common pathological change and necessary way, with abnormal proliferation and excessive extracellular matrix deposition in the liver. The pathological feature of hepatic stellate cells (Hepatic stellate cells, HSCs) of the abnormal activation and secretion of fibrosis factor is an important cause of liver fibrosis. Research shows that a variety of cytokines and MI RNAs plays an important role in the occurrence and development of liver fibrosis? IL-22 can be secreted by a variety of immune cells with IL-22 receptors on cell surface, intracellular signaling and transcription factor activation (signal transducer and activator of transcription, STAT.Mi) play a role in regulating RNAs through the target m RNA complete or incomplete pairing of silencing complex, at the post transcriptional level of gene transcription of the negative regulation of.Mi R-200a in liver fibrosis patients and The fiber model in mouse liver were down regulated, and exert inhibitory effect on HSCs activity by inhibition of target gene. Our previous studies have found that IL-22 can inhibit HSCs activity and play a preventive effect against liver fibrosis in mice, but whether IL-22 and MI R-200a have interaction relationship? If there is, how the changes of related cytokines and their relationship are not? Study? In order to further understand the mechanism of IL-22 and MI R-200a in anti hepatic fibrosis, and to elucidate the interaction of IL-22 and MI R-200a in hepatic fibrosis (cross-talk), and to explore a new therapeutic target for liver fibrosis, this research applied HSCs and liver fibrosis rat model, treated with IL-22 and MI R-200a the intervention respectively, the change detection of downstream factors, interaction was observed between HSCs and hepatic fibrosis in the model. This research will conduct the research from the following three aspects: the first part IL- 22 via the STAT3 pathway to inhibit the activity of HSCs and to study the effect of anti hepatic fibrosis Objective: To observe the effect of IL-22 HSCs after the intervention, the change of cell activity, and to observe the effect of IL-22 on rat liver fibrosis model, to explore the mechanism of IL-22 inhibition and anti liver fiber HSCs activity. Methods: cultured rat HSCs cell line (HSCs-T6) to the logarithmic growth phase, respectively, using 250pg/mL, 500pg/m L, 750pg/m L and 1000pg/m L concentration of IL-22 into the culture medium 48 hour intervention; using 0,2,5ng/m L concentration of TGF- beta 1 is added to the medium 24 hours to activate HSCs; CCK8 method to detect cell proliferation rate, cell apoptosis was detected by flow cytometry, ELISA assay the culture supernatant of alpha smooth muscle actin (-smooth muscle alpha actin, alpha -SMA) and collagen I (Col I) expression level of STAT3 and p-STAT3 protein expression in Western-blot cell was detected by using intraperitoneal injection of CCL4 large; In 8 weeks to build rat liver fibrosis model in IL-22 was given by intraperitoneal injection for 1 weeks, the rats were killed to collect liver tissue, liver pathological changes were observed in mice HE and Masson staining, according to the Ishak scoring system to assess the degree of liver fibrosis; immunohistochemical staining of liver tissue in alpha -SMA, Western-blot detection of liver group the expression of STAT3 and p-STAT3 protein level. Results: with the increase of IL-22 concentration, decreased the proliferation of HSCs to 750 pg/m L, and there was significant difference compared with IL-22 without intervention (P0.05). But with the increasing of IL-22 concentration, apoptosis rate of HSCs had no significant change in supernatant were determined by.ELIAS method in a -SMA and Col I with the increase of IL-22 concentration decreased to 750pg/m L, there was statistical significance level a -SMA with and without IL-22 intervention compared to the difference (P0.05); with the increase of TGF- beta 1 concentration, the rate of rise of the proliferation of HSCs ng/m to 5 L, the proliferation of HSCs The rate of TGF- beta 1 compared with no intervention was statistically significant (P0.05) the expression level of.STAT3 protein with TGF- beta 1 concentration did not change significantly, while the expression level of p-STAT3 protein decreased with increasing concentration of TGF- beta 1, 5ng/m to L, the expression level of p-STAT3 protein than non TGF- beta 1 intervention decreased significantly. The difference was statistically significant (P0.05); the TGF- beta 1 pretreatment HSCs, then use IL-22 respectively after the intervention, the expression level of STAT3 protein did not change significantly, while p-STAT3 protein expression level increased significantly (P0.05); experimental rat model, compared with no IL-22 intervention, the intervention of IL-22, hepatic fibrosis rats significantly improvement of liver Ishak histological scores revealed a statistically significant difference (P0.05) in liver tissue, the expression level of STAT3 protein did not change significantly, while p-STAT3 protein expression level increased significantly (P0.05). Conclusion: IL-22 in a concentration dependent inhibition of HSCs The proliferation and activity, but had no significant effect on HSCs apoptosis; IL-22 can inhibit HSCs activity and anti hepatic fibrosis, its mechanism is activated through phosphorylation of STAT3 signaling pathway expression. The second part of the miR-200a targeting beta -catenin inhibit the proliferation and activity of HSCs Objective: to detect the expression of HSCs and miR-200a in hepatic fibrosis the expression of miR-200a, and observe the effect on HSCs; miR-200a verification of direct regulation of beta -catenin, and verified in HSCs, to clarify the mechanism of targeting miR-200a beta -catenin inhibit the proliferation and activity of HSCs. Methods: HSCs cultured to the logarithmic incubation period, respectively using 0,5ng/m L concentration of TGF- beta 1 into the culture medium 24 intervention hours, the fluorescent quantitative PCR method was used to detect HSCs miR-200a expression in mimics transfected by miR-200a; HSCs lentivirus packaging, observed the expression of HSCs in miR-200a on the impact of HSCs; CCK8 assay Measuring the rate of cell proliferation, cell apoptosis was detected by flow cytometry, alpha -SMA in the supernatant of ELISA cell culture to detect expression levels, the expression level of Western-blot cells detected in beta -catenin protein. The use of online database Targetscan prediction of miR-200a target genes, using dual luciferase reporter system to verify the miR-200a of beta -catenin direct regulation results TGF- beta 1 after activation, the expression level of HSCs in miR-200a was significantly decreased, and TGF- beta 1 activation had significant difference (P0.05). The use of lentiviral packaging miR-200a mimics culture medium was transfected into HSCs rats, compared with no miR-200a transfected HSCs, HSCs transfected miR-200a, the expression of miR-200a increase hit more than 8 times; found that the decline in the rate of HSCs proliferation by CCK8, compared with no miR-200a mimics had significant difference (P0.05) of.ELIAS showed that the miR-200a mimics after transfection, HSCs The culture supernatant of alpha -SMA decreased, compared with no miR-200amimics difference was statistically significant (P0.05). Dual luciferase system display miR-200a transfected with -catenin plasmid mimics and beta cells, luciferase activity was significantly decreased (P0.05); HSCs miR-200a mimics Western-blot showed that after transfection, the expression level of -catenin protein beta decreased (P0.05). Conclusion: miR-200a in activation of HSCs expression decreased in the process, overexpression of miR-200a can inhibit the proliferation and activity of HSCs; dual luciferase reporter system to verify the beta -catenin is a direct target gene miR-200a; miR-200a inhibits the proliferation and activity of HSCs to -catenin by regulation of beta target. The aim of the third part IL-22 interacts with miR-200a in HSCs and liver fibrous tissue in the study: observe the effect of IL-22 and HSCs in hepatic fibrosis of rats and the inhibition of miR-200a, HSCs and liver fibrosis tissues IL The expression of -22 and miR-200a downstream factor, IL-22 and miR-200a in HSCs and elucidate the interaction mechanism of hepatic fibrosis. Methods: IL-22 HSCs treated cells, fluorescence quantitative PCR and Western-blot were used to detect the expression of miR-200a and -catenin in the beta cell; lentiviral transfection of miR-200a inhibitors to HSCs, the inhibition of HSCs miR-200a expression. Then given IL-22 intervention, observe the inhibition effect of IL-22 on miR-200a, HSCs, -SMA alpha ELISA in the supernatant of cell culture to detect the expression level of cells was detected by Western-blot; the expression of STAT3 and p-STAT3 protein levels. By intraperitoneal injection of CCL4 in rats for 4 weeks to construct rat liver fibrosis model in IL-22 was given by intraperitoneal injection at the same time. Given intravenous injection of lentivirus packaging miR-200a inhibitors, rats were killed after 1 weeks, collect the liver tissue, inhibit liver fibrosis in a rat model of miR-200a, HE and Masson staining To observe the pathological changes of liver in mice and color grading system to assess the degree of liver fibrosis by Ishak; immunohistochemical staining of liver tissue in alpha -SMA, Western-blot detection of liver in group -catenin beta, STAT3 and p-STAT3 protein expression observed after inhibition of miR-200a, effects of IL-22 on hepatic fibrosis in rats; results: TGF- beta 1 to activate the activity of HSCs in medium, in the given IL-22 intervention, and found no IL-22 intervention compared to HSCs increased the level of miR-200a in IL-22 after the intervention, and the beta -catenin protein level; the expression of -catenin protein in miR-200a transfected with inhibitors was significantly increased in HSCs (P0.05), the expression level of STAT3 protein had no significant change. But the expression of p-STAT3 protein was significantly decreased (P0.05); the successful construction of rat liver fibrosis model, divided into IL-22 and miR-200a inhibitors and IL-22+miR-200a inhibit single injection group Ors injection group, liver tissue miR-200a transfected with inhibitors in miR-200a expression than non transfected miR-200a inhibitors low, IL-22 anti fibrosis effect by miR-200a inhibition of inhibitors beta -catenin protein expression level was also increased (P0.05), the expression level of STAT3 protein did not change significantly, but the expression of p-STAT3 protein was significantly decreased (P0.05). Conclusion: IL-22 can be up-regulated in HSCs miR-200a, and downregulation of -catenin expression; inhibition of miR-200a expression can inhibit effect of IL-22 on HSCs, and the inhibition of the phosphorylation of STAT3; IL-22 improved hepatic fibrosis in rats by miR-200a inhibitors inhibited the phosphorylation of STAT3 was inhibited.

【學位授予單位】：廣西醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R575.2

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