本文選題：藥物性肝損傷　切入點(diǎn)：臨床特點(diǎn)　出處：《安徽醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：目的:(1)總結(jié)藥物性肝損傷(DILI)的臨床特點(diǎn),探討評估DILI預(yù)后的因素。(2)探討內(nèi)質(zhì)網(wǎng)應(yīng)激(ERS)在利福平(RFP)合用異煙肼(INH)致大鼠肝損傷中的作用及可能機(jī)制。方法:(1)回顧性分析近5年我院DILI的臨床資料,運(yùn)用Logistic回歸分析篩選影響預(yù)后的指標(biāo)。(2)將32只SPF級雄性Sprague-Dawley(SD)大鼠隨機(jī)分成4組,每組8只。正常對照組(N組):予以等量的生理鹽水每日定時空腹灌胃一次;RFP組(R組):給予RFP 50mg·kg-1·d-1定時空腹灌胃一次;模型組(M組):INH和RFP各50mg·kg-1·d-1定時空腹灌胃一次;PBA組:INH和RFP同M組,再給予4-苯基丁酸(PBA)160mg·kg-1·d-1腹腔注射一次;R組和M組給予等量溶劑腹腔注射。連續(xù)14d后處死大鼠。留取大鼠血液和肝臟組織標(biāo)本。全自動生化分析儀檢測大鼠血清中堿性磷酸酶(ALP)、總膽紅素(TBIL)、直接膽紅素(DBIL)、谷丙轉(zhuǎn)氨酶(ALT)、谷草轉(zhuǎn)氨酶(AST)、總膽汁酸(TBA)水平。HE染色觀察大鼠肝臟病理學(xué)改變。免疫印跡法檢測大鼠肝臟葡萄糖調(diào)節(jié)蛋白(GRP78)、P65、IκB及膽鹽輸出泵(Bsep)蛋白的表達(dá)變化。免疫組化法檢測Bsep蛋白在大鼠肝細(xì)胞中的表達(dá)及定位變化。結(jié)果:DILI患者女性較多(57.5%),平均年齡52歲,用藥以中藥、抗菌類及解熱鎮(zhèn)痛類為主。肝細(xì)胞型DILl多見(81.1%),嚴(yán)重程度分級中以中度居多(54.7%),91.5%患者預(yù)后良好。不同嚴(yán)重程度肝細(xì)胞型DILI間Hy's法則符合率不同(P0.05),符合此法則的肝細(xì)胞型DILI患者肝衰竭的發(fā)生率為22.9%(11/48)。多因素回歸分析顯示:影響DILI預(yù)后的指標(biāo)有ALT(OR=1.672,P=0.026)、國際標(biāo)準(zhǔn)化比值(INR)(OR=8.852,P=0.015)。(2)與N組相比,R組、M組大鼠血清TBIL、DBIL、TBA及ALP均升高(P0.05),ALT及AST升高不明顯(P0.05);R組大鼠肝臟病理學(xué)檢查可見肝細(xì)胞脂肪變性,M組可見肝細(xì)胞脂肪變性程度加重、部分可見炎細(xì)胞浸潤和點(diǎn)灶狀壞死;R組、M組大鼠肝臟中GRP78和P65蛋白的表達(dá)量明顯上升(P0.05),IκB及Bsep蛋白的表達(dá)明顯下降(P0.05)。R組、M組肝胞膜上Bsep的平均積分光密度(IOD)分別為3.56±1.18和2.35±1.18,較正常組(9.63±1.59)下降(P0.05),M組肝胞膜上Bsep分布不規(guī)則。與M組相比,PBA組大鼠TBIL、DBIL、ALP及TBA均降低(P0.05);肝臟病理學(xué)變化亦明顯改善;GRP78、P65明顯下調(diào),IκB及Bsep明顯上調(diào)(P0.05);肝胞膜上Bsep的平均IOD值為4.66±1.75,較M組上升(P0.05),肝胞膜上Bsep分布較M組規(guī)則。結(jié)論:(1)DILI患者大部分預(yù)后較好。發(fā)病時ALT及INR是預(yù)測DILI預(yù)后的獨(dú)立指標(biāo)。(2)RFP可導(dǎo)致膽汁淤積和肝細(xì)胞脂肪變性,上調(diào)GRP78、P65及下調(diào)Bsep、IκB蛋白的表達(dá),減少肝細(xì)胞膜上的Bsep并改變其定位。(3)PBA可改善RFP合用INH所致的肝損傷,下調(diào)GRP78、P65及上調(diào)Bsep、IκB蛋白的表達(dá),改善肝細(xì)胞膜上Bsep的表達(dá)和定位,提示ERS在RFP合用INH誘導(dǎo)的大鼠肝損傷中發(fā)揮重要作用,其可能機(jī)制是通過激活NF-κB,抑制Bsep表達(dá)和改變Bsep的定位。
[Abstract]:Objective to summarize the clinical features of drug induced liver injury (DILI). To evaluate the prognostic factors of DILI. (2) to explore the role and possible mechanism of endoplasmic reticulum stress (ERS) in liver injury induced by rifampicin and isoniazid in rats. Methods: 1) the clinical data of DILI in our hospital in recent 5 years were analyzed retrospectively. 32 SPF male Sprague-Dawley SD rats were randomly divided into 4 groups by Logistic regression analysis. Each group (n = 8): the control group (n = 8) was given the same amount of normal saline once a day, the group R was given RFP 50mg 路kg-1 路d -1, the model group was given RFP 50mg 路kg-1 路d -1, and the model group was given RFP 50 mg 路kg-1 路d -1 respectively. The rats in group R and group M were given intraperitoneal injection of the same amount of solvent once a time. The rats were killed after 14 days. Blood and liver tissue samples were collected from the rats. The serum alkaloids in rats were detected by automatic biochemical analyzer. The levels of ALPN, Tbilirubin, direct bilirubin, alanine aminotransferase (alt), glutamic oxalacetic transaminase (AST), total bile acid (TBA) in rats were observed by HE staining. The changes of liver pathology were observed by HE staining. The levels of Glucose-regulated protein GRP78P65I 魏 B in rat liver were detected by Western blot. The expression and localization of Bsep protein in rat hepatocytes were detected by immunohistochemical method. Results the average age was 52 years. Medicine with Chinese medicine, Antibacterial and antipyretic analgesic types were predominant. The majority of hepatocyte DILl was 81.1%, and 91.5% of the patients with moderate severity grade had a good prognosis. The coincidence rate of Hy's rule among DILI patients with different severity was different (P 0.05%), and the hepatocyte according with this rule was found. The incidence of liver failure in patients with type I DILI was 22.9 / 48. The multivariate regression analysis showed that the prognostic indexes of DILI were as follows: ALT OR1. 672% P0. 026, and international standard ratio INR OR8. 852% P0. 015. 0. 2) compared with group N, the serum levels of TBA and ALP in group R M were significantly higher than those in group N. The levels of serum TBA and AST in group R were not significantly higher than those in group R (P 0. 05 and P 0. 05). Histopathological examination of rat liver showed that the degree of fatty degeneration of hepatocytes was aggravated in group M. The expression of GRP78 and p65 protein in the liver of rats in group R and group R were significantly increased. The expression of I 魏 B and Bsep protein in P0.05 group was significantly decreased. The mean integrated optical density of Bsep on liver membrane in group R was significantly lower than that in group C (P 0.05). 3. 56 鹵1. 18 and 2. 35 鹵1. 18, compared with the normal group (9. 63 鹵1. 59), the distribution of Bsep on liver membrane was irregular in P0. 05 + M group. Compared with the M group, the ALP and TBA of TBILD ILN in the PBA group decreased significantly (P 0. 05), and the pathological changes of the liver also improved obviously the downregulation of I 魏 B and Bsep in the liver membrane, and the up-regulation of Bsep on the membrane of the liver. The average IOD value was 4.66 鹵1.75, which was higher than that in M group (P 0.05), and the distribution of Bsep on liver membrane was more regular than that in M group. Conclusion most of the patients with DILI have better prognosis. ALT and INR are independent markers for predicting the prognosis of DILI, which can lead to cholestasis and fatty degeneration of hepatocytes. Upregulation of GRP78 p65 and down-regulation of BsepI 魏 B protein, reduction of Bsep on liver cell membrane and alteration of its localization could improve liver injury induced by RFP combined with INH, down-regulate the expression of BsepI 魏 B protein, and improve the expression and localization of Bsep on liver cell membrane, and down-regulate the expression of BsepI 魏 B protein, down-regulate the expression of GRP78-p65 and up-regulate the expression of BsepI 魏 B protein, and improve the expression and localization of Bsep on liver cell membrane. The results suggest that ERS plays an important role in liver injury induced by RFP combined with INH in rats. The possible mechanism is to inhibit the expression of Bsep and change the location of Bsep by activating NF- 魏 B.
【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R575

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