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不同年齡和性別影響對乙酰氨基酚急性肝損傷敏感性差異的機制研究

發(fā)布時間:2018-01-05 17:25

  本文關(guān)鍵詞:不同年齡和性別影響對乙酰氨基酚急性肝損傷敏感性差異的機制研究 出處:《安徽醫(yī)科大學(xué)》2017年博士論文 論文類型:學(xué)位論文


  更多相關(guān)文章: 對乙酰氨基酚 肝損傷 年齡 性別 Toll樣受體4


【摘要】:背景/目的對乙酰氨基酚(APAP)是臨床上兒童常見的解熱鎮(zhèn)痛藥物,其過量或不當(dāng)使用引起的急性肝臟損傷是兒童藥物性肝損傷的常見原因之一。然而,目前關(guān)于兒童和成人之間APAP急性肝損傷是否存在差異報道甚少。既往研究表明APAP在肝細胞內(nèi)經(jīng)P450代謝酶CYP2E1代謝生成有毒產(chǎn)物N-乙酰對苯醌亞胺(NAPQI),耗竭胞內(nèi)還原型谷胱甘肽(GSH)進而引起氧化應(yīng)激、線粒體功能障礙并最終導(dǎo)致肝細胞死亡。近期研究提示,APAP急性肝損傷過程發(fā)生二次打擊,TLR4信號可能介導(dǎo)APAP急性肝損傷“二次打擊”過程中肝細胞程序性壞死。本課題比較不同年齡和性別小鼠對APAP急性肝損傷的敏感性差異,為今后更好地指導(dǎo)不同人群APAP肝損傷的臨床治療提供理論依據(jù);比較野生型(C3H/He N)與TLR4突變型(C3H/He J)小鼠APAP肝損傷的差異,初步探討TLR4在APAP急性肝損傷不同階段的作用。方法研究一、不同年齡和性別小鼠對APAP急性肝損傷的敏感性差異由兩個實驗組成:實驗一、幼年(3周)CD-1小鼠(雌、雄各10只)和成年(8周)CD-1小鼠(雌、雄各10只)分成四組:幼年雄性小鼠、幼年雌性小鼠、成年雄性小鼠和成年雌性小鼠,每組各10只小鼠。所有小鼠統(tǒng)一禁食12小時后經(jīng)腹腔注射給予單劑量APAP(300mg/kg),觀察各組小鼠生存情況至APAP給藥后的第7天。繪制各組生存曲線并比較各組小鼠生存率差異。實驗二、幼年(3周)CD-1小鼠(雌、雄各40只)和成年(8周)CD-1小鼠(雌、雄各40只)各分成APAP給藥組和對照組。所有小鼠統(tǒng)一禁食12小時。所有APAP給藥組小鼠經(jīng)腹腔注射給予APAP(300mg/kg),對照組給予生理鹽水。給藥后不同時點(第0,1,4和24小時及第7天)剖殺小鼠,比較各組肝指數(shù),檢測血清ALT和肝臟GSH、GSSG與GSSG/GSH水平,用HE染色以觀察組織肝臟病理學(xué)損傷,用TUNEL檢測肝細胞死亡,用免疫組化檢測肝臟硝化酪氨酸(3-NT);用實時定量RT-PCR檢測肝臟Cyp1a1、Cyp2e1、Cyp3a11、Ugt1a1、Gpx、Gr和Gst基因表達水平;用試劑盒檢測肝臟GPX、GR和GST活性;用Western blot檢測肝臟CYP2E1、p-JNK、JNK、RIP1和RIP3蛋白水平。研究二、TLR4在APAP急性肝損傷發(fā)生過程中的作用由兩個實驗組成:實驗一、野生型(C3H/He N)小鼠和突變型(C3H/He J)小鼠各10只,統(tǒng)一禁食12小時后給予APAP(300mg/kg)單劑量腹腔注射,觀察各組小鼠生存情況至APAP給藥后72 h。繪制兩組小鼠生存曲線并比較兩組小鼠生存率的差異。實驗二、野生型(C3H/He N)小鼠和突變型(C3H/He J)小鼠各分成APAP給藥組和對照組。所有小鼠統(tǒng)一禁食12小時。APAP給藥組小鼠經(jīng)腹腔注射給予APAP(300mg/kg),對照組給予等體積生理鹽水。給藥后不同時點(第0,4和12 h)剖殺小鼠,比較兩組小鼠肝指數(shù),檢測血清ALT水平,用HE染色以觀察肝臟病理學(xué)損傷,用TUNEL檢測肝細胞死亡,用Western blot檢測肝臟p-JNK、JNK以及程序性壞死相關(guān)蛋白激酶RIP1、RIP3蛋白的表達。結(jié)果幼年小鼠APAP急性肝損傷較同性別成年小鼠更嚴重。小鼠生存實驗結(jié)果提示,雄性或雌性幼年小鼠生存率(雄性50%、雌性60%)均顯著低于成年小鼠(雄性80%、雌性90%)。進一步觀察發(fā)現(xiàn),與同性別成年小鼠相比,給藥后4小時幼年小鼠肝指數(shù)和血清ALT水平上升更明顯,組織病理學(xué)觀察到肝臟充血明顯;至給藥后24小時雄性和雌性幼年小鼠血清ALT水平仍明顯高于同性別成年小鼠,組織病理學(xué)觀察到肝臟呈小葉中心性壞死,且幼年小鼠肝臟壞死面積明顯大于同性別成年小鼠;TUNEL檢測顯示,幼年小鼠肝臟TUNEL陽性細胞數(shù)明顯高于同性別成年小鼠;免疫印跡實驗結(jié)果顯示,APAP處理后幼年小鼠肝臟p-JNK和RIP3的蛋白水平均明顯高于同性別成年小鼠。免疫組化顯示,APAP處理后4小時和24小時幼年小鼠肝臟硝化酪氨酸(3-NT)陽性細胞數(shù)明顯多于同性別成年小鼠。為探討幼年小鼠對APAP肝損傷更敏感的機制,比較了不同年齡和性別小鼠肝臟APAP代謝酶水平和GSH代謝情況。結(jié)果顯示,與同性別成年小鼠相比,幼年小鼠在APAP給藥后肝臟GSH耗竭量更大,GSSG/GSH比值上升更明顯;進一步分析發(fā)現(xiàn),幼年小鼠肝臟Cyp2e1、Cyp3a11的m RNA水平和CYP2E1蛋白含量均較同性別成年小鼠更高。本課題發(fā)現(xiàn),APAP急性肝損傷性別差異只存在于成年小鼠,成年雄性小鼠APAP急性肝損傷較成年雌性小鼠更嚴重。APAP處理后4小時和24小時成年雄性小鼠血清ALT水平均高于成年雌性小鼠;組織病理學(xué)觀察到成年雄性小鼠肝臟壞死面積明顯大于成年雌性小鼠;TUNEL檢測提示,成年雄性小鼠肝臟TUNEL陽性細胞數(shù)明顯高于成年雌性小鼠。進一步觀察發(fā)現(xiàn),APAP處理后4小時成年雄性小鼠肝臟p-JNK水平明顯高于成年雌性小鼠;免疫組化顯示,APAP處理后4小時和24小時成年雄性小鼠肝臟3-NT陽性細胞數(shù)明顯多于成年雌性小鼠。APAP處理后4小時成年雄性小鼠肝臟GSH消耗量較成年雌性小鼠大,且GSSG/GSH比值恢復(fù)速度明顯慢于成年雌性小鼠;成年雄性小鼠肝臟GPX和GST活性均低于成年雌性小鼠。野生型(C3H/He N)小鼠APAP急性肝損傷較突變型(C3H/He J)小鼠更嚴重。72h生存曲線結(jié)果提示野生型(C3H/He N)小鼠給藥4小時后即發(fā)生死亡,72小時生存率為40%;(C3H/He J)小鼠至給藥8小時才發(fā)生死亡,72小時生存率為70%。故野生型(C3H/He N)小鼠較突變型(C3H/He J)小鼠生存率低。APAP處理4 h后,C3H/He N小鼠肝指數(shù)較C3H/He J小鼠上升明顯。給藥4 h和12 h,C3H/He N小鼠血清ALT水平均較C3H/He J小鼠高。肝臟HE染色提示,C3H/He N小鼠肝臟壞死面積較大。肝臟TUNEL結(jié)果提示,C3H/He N小鼠肝臟TUNEL+陽性細胞數(shù)明顯多于C3H/He J小鼠。C3H/He N小鼠在給藥后的4 h和12 h,肝臟p-JNK的表達均高于C3H/He J小鼠。給藥后4 h,C3H/He N小鼠肝臟RIP1的表達高于C3H/He J小鼠;給藥后12 h,C3H/He N小鼠肝臟RIP1的表達與C3H/He J小鼠無差異,但肝臟RIP3的表達明顯高于C3H/He J小鼠。結(jié)論不同年齡小鼠對APAP急性肝損傷存在敏感性差異,幼年小鼠更易于發(fā)生APAP急性肝臟損傷。其機制可能與幼年小鼠肝臟Cyp2e1、Cyp3a11的m RNA水平和CYP2E1蛋白含量均較同性別成年小鼠更高;幼年小鼠對于APAP引起的肝臟GSH耗竭更敏感;APAP處理后幼年小鼠肝臟P-JNK和RIP3蛋白表達更高有關(guān)。APAP急性肝損傷的性別差異只存在于成年小鼠,具體表現(xiàn)為成年雄性小鼠比成年雌性小鼠肝臟損傷更明顯。其機制可能與成年雄性小鼠肝臟GSH代謝酶(GPX和GST)活性比成年雌性小鼠低,APAP處理后成年雄性小鼠肝臟GSH消耗多,進而抗氧化以及促進有毒代謝產(chǎn)物的排出能力降低,加劇肝細胞JNK持續(xù)性激活,繼而導(dǎo)致肝臟損傷加重。在APAP急性肝損傷早期,野生型(C3H/He N)小鼠APAP肝臟損傷較突變型(C3H/He J)小鼠嚴重,提示TLR4基因突變在APAP急性肝損傷早期中起到保護作用,推測肝臟TLR4信號通路參與激活肝臟JNK、RIP1和RIP3,促進肝細胞程序性壞死。
[Abstract]:Background / purpose of acetaminophen (APAP) is a clinically common antipyretic analgesic drugs, the excessive or improper use of acute liver injury caused by children is one of the common causes of drug-induced liver injury. However, at present about between adults and children with acute liver injury APAP whether there are some differences are rarely reported. Previous study showed that APAP in the liver cells by P450 metabolic enzyme CYP2E1 metabolism of toxic products of acetyl N- quinone imine (NAPQI), depletion of intracellular glutathione (GSH) caused by oxidative stress, mitochondrial dysfunction and ultimately lead to the death of liver cells. Recent studies suggest that APAP induced acute liver injury during the two attack, TLR4 signaling could be mediated liver cell programmed necrosis APAP induced acute liver injury "two hit" in the process. The subject of sensitivity to APAP induced acute liver injury of mice of different age and gender differences, for this After in order to guide the clinical treatment of APAP in different populations of liver injury and provide a theoretical basis; compared to the wild type (C3H/He N type) and TLR4 (C3H/He J) mutation between APAP liver injury in mice, preliminary study on TLR4 damage in different stages in acute liver APAP. A research method, sensitivity of different age and gender on mice with acute APAP liver injury consists of two experiments: Experiment 1, young (3 weeks) CD-1 mice (female, male = 10) and adult (8 weeks) CD-1 mice (female, male = 10) were divided into four groups: young male mice, immature female mice, adult male mice and adult female mice. With 10 mice in each group. All mice were unified after fasting for 12 hours by intraperitoneal injection with a single dose of APAP (300mg/kg), to observe the survival rate of mice to APAP seventh days after dosing. The survival curves were compared and plotted for each group of mice survival rate difference. In experiment two, the young (3 weeks) CD-1 Mice (female, male = 40) and adult (8 weeks) CD-1 mice (female, male = 40) were divided into APAP treatment group and control group. All mice were fasted for 12 hours. All unified administration of APAP mice by intraperitoneal injection of APAP (300mg/kg), the control group received saline. After treatment at different time points (0,1,4 and 24 hours and 7 days) mice were killed, compared the liver index, serum ALT and liver GSH, GSSG and GSSG/GSH levels, HE staining was used to observe the pathology of liver tissue injury and death with liver cell TUNEL detection, detection of liver tyrosine nitration by immune group (3-NT) the liver was detected by real-time quantitative RT-PCR; Cyp1a1, Cyp2e1, Cyp3a11, Ugt1a1, Gpx, Gr and Gst gene expression levels in the liver; GPX kit, GR and GST activity; with Western blot detection of liver CYP2E1, p-JNK, JNK, RIP1 and RIP3 protein level. Two, TLR4 damage occurred in the process of the in acute liver APAP Composed of two experiments, the wild type (C3H/He N) mice and mutant mice (C3H/He J) 10, unified after 12 hours of fasting for APAP (300mg/kg) single dose intraperitoneal injection, the mice were observed to survival after administration of APAP 72 h. to draw the two groups of mice and survival curve differences in the survival rate of mice were compared between the two groups. In experiment two, wild type mice (C3H/He N) and mutant (C3H/He J) were divided into APAP treatment group and control group. All mice were fasted for 12 hours the unified administration of.APAP group were given intraperitoneal injection of APAP (300mg/kg), the control group received equal volume of physiological saline. After administration at different time points (0,4 and 12 h) mice were sacrificed and the liver index were compared between the two groups, the level of serum ALT detection, using HE staining to observe the pathological liver injury, liver cell death by detection of TUNEL, Western p-JNK and JNK blot detection of liver, programmed necrosis related protein kinase The enzyme RIP1, the expression of RIP3 protein. Results the juvenile mice APAP induced acute liver injury with the same sex of adult mice is more serious. The survival results suggest that male or female juvenile survival rate of mice (male 50%, female 60%) were significantly lower than those in adult mice (male 80%, female 90%). Further observation showed that, compared with the the sex of adult mice, 4 hours after administration of juvenile mice liver index and serum ALT levels increased more significantly, learn to observe liver hyperaemia obvious pathology; and 24 hours after administration of male and female juvenile mice serum ALT levels were still higher than those in same-sex adult mice, histopathological observation to the liver showed centrilobular necrosis, and the young mice liver necrotic area was significantly greater than the sex of adult mice; TUNEL showed that juvenile mice liver TUNEL positive cells was significantly higher than that of sex in adult mice; Western blotting results indicated that APAP After the treatment of protein levels in juvenile mice liver p-JNK and RIP3 were significantly higher than those in same-sex adult mice. Immunohistochemistry showed that APAP treatment after 4 hours and 24 hours of juvenile mice liver nitrotyrosine (3-NT) positive cells were significantly more than the number of same-sex adult mice. To explore the mechanism of juvenile mice are more sensitive to APAP liver injury. Comparison of different age and gender in mouse liver APAP metabolic enzyme levels and GSH metabolism. The results showed that compared with the sex of adult mice, juvenile mice after APAP administration of liver GSH depletion to be larger, the ratio of GSSG/GSH increased more significantly; further analysis found that young mice liver Cyp2e1, Cyp3a11 m RNA and CYP2E1 protein level the content of same sex were higher in adult mice. This study found that APAP induced acute liver injury of gender differences exist only in adult mice, adult male mice APAP acute liver injury compared with adult female mice Serious.APAP 4 hours after treatment and 24 hours of adult male mice serum ALT levels were higher than that of adult female mice; histological observation to adult male mice liver necrosis area was significantly greater than that of adult female mice tissues; TUNEL detection showed that adult male mouse liver TUNEL positive cell number was significantly higher than that of adult female mice. Further observation showed that after treatment with APAP 4 hours of adult male mice liver p-JNK levels were significantly higher than that of adult female mice; immunohistochemistry showed that APAP treatment after 4 hours and 24 hours of adult male mouse liver 3-NT positive cells were significantly more than the number of adult female.APAP mice 4 hours after the treatment of adult male mouse liver GSH consumption than adult female mice, and the ratio of GSSG/GSH recovery was slower in the adult female mice; GPX and GST activity in the liver of adult male mice were lower than adult female mice. The wild type mice (C3H/He N) A A mutant PAP of acute liver injury (C3H/He J) were more severe.72h results suggest that the survival curve of wild type (C3H/He N) mice were administered 4 hours after the occurrence of death, 72 hour survival rate was 40%; (C3H/He J) mice to administration 8 hours before the occurrence of death, 72 hour survival rate is 70%. so wild type (C3H/He N) in mice with mutant (C3H/He J) the survival rate of mice with low.APAP after 4 h treatment, the liver index of N mice C3H/He C3H/He J mice increased significantly. Administration of 4 h and 12 h, the level of serum ALT C3H/He N mice than C3H/He mice. J HE staining showed that the liver C3H/He, N liver necrosis area larger. Liver TUNEL results suggest that C3H/He mouse liver N TUNEL+ positive cells were significantly more than the number of C3H/He J.C3H/He in mice N mice after administration of 4 h and 12 h, the expression of liver p-JNK was higher than C3H/He in J mice. After Administration of 4 h C3H/He N mouse liver RIP1 expression was higher than that of C3H/He J mice; After administration of 12 h, C3H/He RIP1 expression in liver of N mice and C3H/He J mice had no significant difference, but the expression of hepatic RIP3 was significantly higher than that of C3H/He in J mice. Mice of different ages have different sensitivity to the conclusion of APAP induced acute liver injury, juvenile mice are more susceptible to APAP acute liver injury. The possible mechanism and juvenile mouse liver Cyp2e1. Cyp3a11 m RNA CYP2E1 level and protein content were lower than the same sex adult mice were higher; liver GSH depletion for juvenile mice caused by APAP are more sensitive; after APAP treatment, expression of RIP3 protein and P-JNK in mouse liver of juvenile sex differences in acute liver injury more about.APAP exists only in adult mice, the specific performance of adult male mice than adult female mice liver injury is more obvious. The mechanism may be related to adult male mice liver GSH metabolic enzymes (GPX and GST) activity than adult female mice, adult male mice liver after APAP treatment Dirty GSH consumption, and reduce the antioxidant and ability to promote the discharge of toxic metabolites, intensified hepatocyte persistent activation of JNK, and then lead to liver damage. In the early stage of acute liver injury APAP, wild type (C3H/He N) APAP mice liver injury than mutant mice (C3H/He J), suggesting that TLR4 gene mutation plays the protective effect in the early stage of acute hepatic injury in APAP, speculated that the liver TLR4 signaling pathway is involved in activation of liver JNK, RIP1 and RIP3, promote liver cell programmed necrosis.

【學(xué)位授予單位】:安徽醫(yī)科大學(xué)
【學(xué)位級別】:博士
【學(xué)位授予年份】:2017
【分類號】:R725.7

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