本文選題：肝纖維化　切入點(diǎn)：白介素-22　出處：《廣西醫(yī)科大學(xué)》2017年博士論文　論文類型：學(xué)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(xì)胞外基質(zhì)異常增生和在肝內(nèi)過(guò)量沉積為病理特征。肝星狀細(xì)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(xì)胞因子和mi RNAs在肝纖維化的發(fā)生和發(fā)展過(guò)程中扮演著重要角色?IL-22可由多種免疫細(xì)胞分泌,通過(guò)與細(xì)胞表面的IL-22受體結(jié)合后,激活細(xì)胞內(nèi)信號(hào)傳導(dǎo)與轉(zhuǎn)錄激活因子(signal transducer and activator of transcription,STAT)發(fā)揮調(diào)控作用。mi RNAs通過(guò)與靶m RNA完全或不完全配對(duì)形成沉默復(fù)合體,在轉(zhuǎn)錄后水平對(duì)基因轉(zhuǎn)錄進(jìn)行負(fù)調(diào)控。mi R-200a在肝纖維化患者和大小鼠肝纖維模型中均表達(dá)下調(diào),并通過(guò)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I(xiàn)L-22是否與mi R-200a有交互作用關(guān)系?如果有,相關(guān)細(xì)胞因子變化及其相互關(guān)系如何?目前無(wú)相關(guān)研究?為進(jìn)一步了解IL-22和mi R-200a在抗肝纖維化作用的機(jī)制,并闡明IL-22和mi R-200a在肝纖維化中的交互作用(cross-talk)關(guān)系,進(jìn)而探索出肝纖維化新的治療靶點(diǎn),本研究應(yīng)用大鼠HSCs和肝纖維化模型,分別給予IL-22和mi R-200a干預(yù),檢測(cè)相關(guān)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(jìn)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(yù)HSCs后,細(xì)胞活性的改變情況,并觀察IL-22對(duì)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(jī)制。方法:培養(yǎng)大鼠HSCs細(xì)胞系(HSCs-T6)至對(duì)數(shù)生長(zhǎng)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(yù)48小時(shí);分別采用0、2、5ng/m L濃度的TGF-β1加入培養(yǎng)基24小時(shí)激活HSCs;CCK8法檢測(cè)細(xì)胞增殖率,流式細(xì)胞術(shù)檢測(cè)細(xì)胞凋亡率,ELISA檢測(cè)細(xì)胞培養(yǎng)上清液中的α-平滑肌肌動(dòng)蛋白(α-smooth muscle actin,α-SMA)和膠原蛋白I(Col I)表達(dá)水平,western-blot法檢測(cè)細(xì)胞中的STAT3和p-STAT3蛋白表達(dá)水平;采用CCL4腹腔注射大鼠8周構(gòu)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(píng)分系統(tǒng)評(píng)估肝纖維化的程度;免疫組織化學(xué)染色檢測(cè)肝臟組織中α-SMA,western-blot法檢測(cè)肝組中的STAT3和p-STAT3蛋白表達(dá)水平。結(jié)果:隨著IL-22濃度的升高,HSCs增殖率下降,到750 pg/m L時(shí),與無(wú)IL-22干預(yù)相比差異有統(tǒng)計(jì)學(xué)意義(P0.05)。但隨著IL-22濃度的升高,HSCs凋亡率無(wú)顯著改變。ELIAS法檢測(cè)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(shí),α-SMA水平與無(wú)IL-22干預(yù)相比差異有統(tǒng)計(jì)學(xué)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(shí),HSCs的增殖率與無(wú)TGF-β1干預(yù)相比差異有統(tǒng)計(jì)學(xué)意義(P0.05)。STAT3蛋白表達(dá)水平隨著TGF-β1濃度的升高無(wú)顯著改變,而p-STAT3蛋白表達(dá)水平隨著TGF-β1濃度的升高而下降,到5ng/m L時(shí),p-STAT3蛋白表達(dá)水平比無(wú)TGF-β1干預(yù)時(shí)顯著下降,差異有統(tǒng)計(jì)學(xué)意義(P0.05);采用TGF-β1預(yù)處理HSCs,再使用IL-22分別干預(yù)后,STAT3蛋白表達(dá)水平無(wú)顯著改變,而p-STAT3蛋白表達(dá)水平顯著上升(P0.05);大鼠模型實(shí)驗(yàn)中,與未進(jìn)行IL-22干預(yù)相比,IL-22干預(yù)后,大鼠肝纖維化明顯改善,肝臟Ishak組織學(xué)評(píng)分顯示差異有統(tǒng)計(jì)學(xué)意義(P0.05),肝組織中的STAT3蛋白表達(dá)水平無(wú)顯著改變,而p-STAT3蛋白表達(dá)水平顯著上升(P0.05)。結(jié)論:IL-22以濃度依賴性抑制HSCs增殖和活性,但對(duì)HSCs凋亡無(wú)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(jī)制是通過(guò)激活STAT3磷酸化信號(hào)通路表達(dá)實(shí)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(cè)miR-200a在HSCs和肝纖維化組織的表達(dá)情況,并觀察過(guò)表達(dá)miR-200a對(duì)HSCs的影響;驗(yàn)證miR-200a對(duì)β-catenin直接調(diào)控作用,并在HSCs驗(yàn)證,闡明miR-200a靶向β-catenin抑制HSCs增殖與活性的機(jī)制。方法:培養(yǎng)HSCs至對(duì)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(yù)24小時(shí),采用熒光定量PCR法檢測(cè)HSCs中的miR-200a表達(dá)情況;采用慢病毒包裝的miR-200a mimics轉(zhuǎn)染HSCs,觀察過(guò)表達(dá)HSCs中的miR-200a對(duì)HSCs的影響;CCK8法檢測(cè)細(xì)胞增殖率,流式細(xì)胞術(shù)檢測(cè)細(xì)胞凋亡率,ELISA檢測(cè)細(xì)胞培養(yǎng)上清液中的α-SMA表達(dá)水平,western-blot法檢測(cè)細(xì)胞中的β-catenin蛋白表達(dá)水平。使用在線數(shù)據(jù)庫(kù)Targetscan預(yù)測(cè)miR-200a的靶基因,在使用雙熒光素酶報(bào)告系統(tǒng)驗(yàn)證miR-200a對(duì)β-catenin直接調(diào)控作用,結(jié)果:TGF-β1激活后,HSCs中的miR-200a表達(dá)水平顯著下降,與無(wú)TGF-β1激活相比差異有統(tǒng)計(jì)學(xué)意義(P0.05)。使用慢病毒包裝的大鼠miR-200a mimics培養(yǎng)基轉(zhuǎn)染HSCs,與未進(jìn)行miR-200a轉(zhuǎn)染的HSCs相比,轉(zhuǎn)染了miR-200a的HSCs中,miR-200a表達(dá)升高打8倍以上;CCK8法發(fā)現(xiàn)HSCs增殖率下降,與未進(jìn)行miR-200a mimics相比差異有統(tǒng)計(jì)學(xué)意義(P0.05)。ELIAS法發(fā)現(xiàn)miR-200a mimics轉(zhuǎn)染后,HSCs培養(yǎng)上清液中的α-SMA水平下降,與未進(jìn)行miR-200amimics相比差異有統(tǒng)計(jì)學(xué)意義(P0.05)。雙熒光素酶系統(tǒng)顯示轉(zhuǎn)染了miR-200a mimics和β-catenin質(zhì)粒后,細(xì)胞中的熒光素酶活性顯著下降(P0.05);western-blot法顯示HSCs轉(zhuǎn)染miR-200a mimics后,細(xì)胞中的β-catenin蛋白表達(dá)水平下降(P0.05)。結(jié)論:miR-200a在HSCs激活過(guò)程中表達(dá)下降,過(guò)表達(dá)miR-200a可以抑制HSCs增殖和活性;雙熒光素酶系統(tǒng)驗(yàn)證了β-catenin是miR-200a的直接靶基因;miR-200a通過(guò)靶向調(diào)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(yù)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(dá)情況,闡明IL-22與miR-200a在HSCs和肝纖維組織中交互作用機(jī)制。方法:IL-22干預(yù)HSCs后細(xì)胞,熒光定量PCR和western-blot分別檢測(cè)細(xì)胞中miR-200a和β-catenin表達(dá)的情況;慢病毒轉(zhuǎn)染miR-200a inhibitors至HSCs,抑制HSCs中的miR-200a表達(dá),再給予IL-22干預(yù),觀察抑制miR-200a后,IL-22對(duì)HSCs的影響,ELISA檢測(cè)細(xì)胞培養(yǎng)上清液中的α-SMA表達(dá)水平;western-blot法檢測(cè)細(xì)胞中的STAT3和p-STAT3蛋白表達(dá)水平。采用CCL4腹腔注射大鼠4周構(gòu)建大鼠肝纖維化模型,在給予IL-22腹腔注射,同時(shí)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(píng)分系統(tǒng)評(píng)估肝纖維化的程度;免疫組織化學(xué)染色檢測(cè)肝臟組織中α-SMA,western-blot法檢測(cè)肝組中的β-catenin、STAT3和p-STAT3蛋白表達(dá)水平,觀察抑制miR-200a后,IL-22對(duì)大鼠肝纖維化的影響;結(jié)果:TGF-β1加入培養(yǎng)基中激活HSCs活性,在給予IL-22干預(yù),發(fā)現(xiàn)與未進(jìn)行IL-22干預(yù)相比,IL-22干預(yù)后HSCs中的miR-200a水平上升,而β-catenin蛋白水平下降;轉(zhuǎn)染了miR-200a inhibitors的HSCs中β-catenin蛋白表達(dá)水平顯著升高(P0.05),STAT3蛋白表達(dá)水平無(wú)顯著改變,但p-STAT3的蛋白表達(dá)水平明顯下降(P0.05);大鼠肝纖維化模型構(gòu)建成功后,分為IL-22和miR-200a inhibitors單獨(dú)注射組和IL-22+miR-200a inhibitors注射組,轉(zhuǎn)染了miR-200a inhibitors的肝組織中的miR-200a表達(dá)比未轉(zhuǎn)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(dá)水平也較升高(P0.05),STAT3蛋白表達(dá)水平無(wú)顯著改變,但p-STAT3的蛋白表達(dá)水平明顯下降(P0.05)。結(jié)論:IL-22可以上調(diào)HSCs中的miR-200a表達(dá)量,進(jìn)而下調(diào)β-catenin表達(dá)水平;抑制miR-200a表達(dá)量可以抑制IL-22對(duì)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(xué)位授予單位】：廣西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R575.2

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