本文選題：膿毒癥 + 肝損傷��； 參考：《重慶醫(yī)科大學(xué)》2016年博士論文

【摘要】：膿毒癥是一種由于感染引起的全身炎性反應(yīng)綜合征,是各種嚴(yán)重創(chuàng)傷、燒傷、或大手術(shù)后常見并發(fā)癥,常導(dǎo)致膿毒癥休克甚至多器官功能障礙綜合征。肝臟不僅是膿毒癥時最易受損的靶器官之一,還在膿毒癥發(fā)生和發(fā)展過程發(fā)揮著舉足輕重的作用。膿毒癥發(fā)生時,肝臟定居的巨噬細(xì)胞-Kupffer細(xì)胞被血中內(nèi)毒素所激活,大量釋放各類炎癥因子,直接導(dǎo)致肝臟炎癥并引發(fā)全身炎癥反應(yīng);Kupffer細(xì)胞和其他炎性細(xì)胞產(chǎn)生大量氧自由基和脂質(zhì)過氧化產(chǎn)物如丙二醛等,引起肝細(xì)胞膜破壞和線粒體功能受損,導(dǎo)致轉(zhuǎn)氨酶和膽紅素等大量釋放入血;同時,膿毒癥時肝臟多種凝血因子、抗凝血因子以及纖溶抑制物合成減少,肝細(xì)胞清除活性因子能力下降,導(dǎo)致機(jī)體凝血功能障礙,進(jìn)一步加劇全身炎癥反應(yīng)和器官損傷。目前認(rèn)為,早期肝功能障礙是膿毒癥患者死亡的一項(xiàng)獨(dú)立的預(yù)警因素,因此對膿毒癥肝損傷患者開展早期有效治療、及時改善肝功能,有助于改善膿毒癥患者預(yù)后。川陳皮素(Nobiletin,5,6,7,8,3',4'-hexame-thoxy flavone),別名川皮亭,又稱蜜橘黃酮,是從蕓香科柑桔屬橘子Citrus reticulaia Blanco果皮中提取的一種多甲氧基黃酮類化合物。近年來研究顯示川陳皮素具有抗炎、抗氧化、抗腫瘤以及神經(jīng)保護(hù)等多種生物活性,其作用可能與抑制NF-kB和激活劑蛋白-1(AP-1)等轉(zhuǎn)錄因子的活性有關(guān),并且沒有明顯的毒副作用。因此,川陳皮素可用于臨床治療多種炎癥性疾病和腫瘤等,具有很大的開發(fā)前景。然而目前為止,川陳皮素的藥理效應(yīng)和抗炎作用機(jī)制并未闡明,能否作為膿毒癥肝損傷的治療用藥也需要進(jìn)一步評價。本研究擬采用內(nèi)毒素誘導(dǎo)小鼠膿毒癥肝損傷的動物模型,觀察川陳皮素治療膿毒癥肝損傷后小鼠死亡率的改變、血清中丙氨酸轉(zhuǎn)氨酶(ALT)、天冬氨酸轉(zhuǎn)氨酶(AST)、總膽紅素(TBil)的水平、血清和肝組織中TNF-α、IL-1β和IL-6的變化,提取Kupffer細(xì)胞并檢測炎癥介質(zhì)i NOS和COX-2的含量改變,同時檢測NF-κB、MAPK(ERK、JNK和p38MAPK)和Nrf2-HO-1信號轉(zhuǎn)導(dǎo)通路的變化等,旨在闡明川陳皮素治療膿毒癥肝損傷的相關(guān)分子機(jī)制,為膿毒癥肝損傷的預(yù)防和臨床治療提供一種新的研究思路。第一部分:川陳皮素對膿毒癥肝損傷小鼠的保護(hù)作用目的:觀察川陳皮素對膿毒癥肝損傷小鼠的保護(hù)作用。方法:利用內(nèi)毒素腹腔注射建立膿毒癥肝損傷小鼠模型。將75只成年C57BL/6小鼠隨機(jī)分為五組:正常對照組(15只,磷酸鹽緩沖液)、LPS模型組(15只,LPS 10mg/kg)、川陳皮素低劑量組(15只,LPS10mg/kg和川陳皮素50mg/kg)、川陳皮素中劑量組(15只,LPS 10mg/kg和川陳皮素100mg/kg)、川陳皮素高劑量組(15只,LPS 10mg/kg和川陳皮素200mg/kg)。各組于腹腔注射藥物后不同時間點(diǎn)(6h、12h、24h)分別處死5只小鼠,收集血液及肝組織標(biāo)本。HE染色觀察肝組織病理形態(tài)變化,測定實(shí)驗(yàn)各組血清中丙氨酸轉(zhuǎn)氨酶(ALT)、天冬氨酸轉(zhuǎn)氨酶(AST)、總膽紅素(TBil)的水平,測定血清和肝組織中TNF-α、IL-1β、IL-6的含量。另外取50只小鼠重復(fù)以上分組,注射藥物后觀察并比較72小時內(nèi)各組小鼠生存率。結(jié)果:與正常對照組相比較,模型組和藥物干預(yù)組各項(xiàng)指標(biāo)均發(fā)生了顯著改變,表明本實(shí)驗(yàn)?zāi)Ｐ蜆?gòu)建成功。(1)LPS注射2h后,模型組和藥物干預(yù)組小鼠均出現(xiàn)精神萎靡、觸之不動、呼吸急促、體溫下降、不進(jìn)食水等表現(xiàn),而NOB干預(yù)組小鼠的精神和狀態(tài)相對較好;(2)LPS注射后24h后,小鼠肝臟出現(xiàn)明顯病理改變,組織細(xì)胞腫脹、壞死、充血和炎性細(xì)胞浸潤,但NOB干預(yù)組組織損傷明顯緩解;(3)模型組血清中ALT、AST和TBil水平較正常對照明顯升高,而NOB干預(yù)組中以上指標(biāo)明顯下降(P0.05或P0.01);(4)模型組血清中和肝臟勻漿中炎癥因子TNF-α、IL-1β和IL-6的含量明顯升高,而NOB干預(yù)組中以上指標(biāo)明顯下降(P0.05或P0.01);(5)正常對照組、模型組及NOB干預(yù)組72h生存率觀察發(fā)現(xiàn),正常對照組生存率為100%,模型組小鼠72h生存率為0%,NOB干預(yù)組能有效提高膿毒癥小鼠72h生存率:其中50mg/kg劑量組72h生存率為40%;100mg/kg劑量組72h生存率為50%;200mg/kg劑量組72h生存率為80%;結(jié)論:川陳皮素通過抑制膿毒癥全身和肝臟炎癥因子釋放,減輕肝臟肝細(xì)胞水腫、壞死和抑制炎性細(xì)胞浸潤,減少肝酶的釋放,進(jìn)而對膿毒癥肝損傷小鼠發(fā)揮保護(hù)作用,最終顯著提高小鼠的生存率。第二部分:川陳皮素對LPS活化的小鼠Kupffer細(xì)胞IkB/NF-kB信號通路的影響目的:通過觀察川陳皮素對LPS活化的小鼠Kupffer細(xì)胞IkB/NF-kB信號通路的影響,闡明川陳皮素在膿毒癥肝損傷保護(hù)作用的分子機(jī)制。方法:采用離體膠原酶消化、密度梯度離心聯(lián)合選擇性貼壁法分離Kupffer細(xì)胞,接種于六孔板,隨機(jī)分為五組:正常對照組(磷酸鹽緩沖液)、LPS模型組(LPS 10μg/ml)、川陳皮素低劑量組(LPS 10μg/ml和川陳皮素10μM)、川陳皮素中劑量組(LPS 10μg/ml和川陳皮素20μM)、川陳皮素高劑量組(LPS 10μg/ml和川陳皮素40μM)。藥物刺激后分別在1h收取細(xì)胞和12h收取細(xì)胞培養(yǎng)上清,進(jìn)行如下檢測:ELISA檢測12h時細(xì)胞培養(yǎng)上清細(xì)胞因子TNF-α、IL-1β、IL-6水平;Western blotting檢測1h時Kupffer細(xì)胞p-IkB、IkB、p-p65、p65蛋白變化;EMSA檢測Kupffer細(xì)胞核內(nèi)NF-kB p65的DNA結(jié)合活力。結(jié)果:LPS刺激體外培養(yǎng)的Kupffer細(xì)胞12h后,細(xì)胞培養(yǎng)上清中炎癥因子TNF-α、IL-1β、IL-6的含量顯著增加,而不同劑量川陳皮素干預(yù)后上述炎癥因子含量顯著下降(P0.05或P0.01);LPS刺激1h后,Kupffer細(xì)胞中p-IkB/IkB、p-p65/p65蛋白比例明顯增高(P0.05或P0.01),細(xì)胞核內(nèi)NF-kB p65的DNA結(jié)合活力也明顯增加(P0.05或P0.01),而不同劑量川陳皮素干預(yù)后上述指標(biāo)顯著下降(P0.05或P0.01)。結(jié)論:川陳皮素對膿毒癥肝損傷的保護(hù)作用可能與抑制Kupffer細(xì)胞IkB/NF-kB信號通路的過度活化、減少相關(guān)炎癥因子的蛋白表達(dá)有關(guān)。第三部分:川陳皮素對LPS活化的小鼠Kupffer細(xì)胞MAPK和Nrf2-HO-1信號通路的影響目的:通過觀察川陳皮素對LPS活化的小鼠Kupffer細(xì)胞MAPK(ERK、JNK和p38MAPK)和Nrf2-HO-1信號通路的影響,探索川陳皮素對膿毒癥肝損傷保護(hù)作用的分子機(jī)制。方法:采用離體膠原酶消化、密度梯度離心聯(lián)合選擇性貼壁法分離Kupffer細(xì)胞,接種于六孔板,隨機(jī)分為五組:正常對照組(磷酸鹽緩沖液)、LPS模型組(LPS 10μg/ml)、川陳皮素低劑量組(LPS 10μg/ml和川陳皮素10μM)、川陳皮素中劑量組(LPS 10μg/ml和川陳皮素20μM)、川陳皮素高劑量組(LPS 10μg/ml和川陳皮素40μM)。藥物刺激后分別在1h、6h、12h收取細(xì)胞,Western blotting檢測細(xì)胞p-ERK、p-JNK、p-p38MAPK、Nrf2、HO-1、i NOS、COX-2表達(dá)蛋白變化。結(jié)果:LPS刺激體外培養(yǎng)的Kupffer細(xì)胞1h后,p-ERK、p-JNK、p-p38MAPK的表達(dá)相比正常對照組明顯增高(P0.05或P0.01),而不同劑量川陳皮素干預(yù)后上述指標(biāo)顯著下降(P0.05或P0.01);LPS刺激6h后,細(xì)胞漿HO-1和細(xì)胞核Nrf2蛋白表達(dá)相比正常對照組輕微升高,而不同劑量川陳皮素干預(yù)后上述指標(biāo)顯著升高(P0.05或P0.01);LPS刺激12h后,細(xì)胞i NOS和COX-2蛋白表達(dá)相比正常對照組明顯增高(P0.05或P0.01),而不同劑量川陳皮素干預(yù)后上述指標(biāo)顯著下降(P0.05或P0.01)。結(jié)論:川陳皮素對膿毒癥肝損傷的保護(hù)作用可能與抑制Kupffer細(xì)胞MAPK(ERK、JNK和p38 MAPK)信號通路過度活化、減少炎癥介質(zhì)i NOS和COX-2的表達(dá)和激活Nrf2-HO-1抗氧化通路有關(guān)。
[Abstract]:Sepsis is a systemic inflammatory response syndrome caused by infection, which is a common complication of severe trauma, burns, or major surgery, often leading to septic shock and even multiple organ dysfunction syndrome. The liver is not only one of the most vulnerable target organs in sepsis, but also plays a foot in the pathogenesis and development of sepsis. When sepsis occurs, the macrophage -Kupffer cells that are settled in the liver are activated by the endotoxin in the blood and release a large number of inflammatory factors, which directly cause inflammation of the liver and cause systemic inflammatory reactions; Kupffer cells and other inflammatory cells produce a large number of oxygen free radicals and lipid peroxidation products, such as malondialdehyde, which cause liver fine. The destruction of the membrane and the damage of the mitochondrial function caused the release of aminotransferase and bilirubin into the blood. At the same time, the synthesis of a variety of coagulant factors, anticoagulant factors and fibrinolytic inhibitors in the liver decreased, the ability to scavenging active factors of liver cells decreased, causing the body coagulation dysfunction and further aggravating systemic inflammatory response and organ damage. It is now considered that early liver dysfunction is an independent early warning factor for the death of sepsis, so early effective treatment for patients with sepsis and liver injury, timely improvement of liver function, can help improve the prognosis of sepsis patients. Nobiletin, 5,6,7,8,3', 4'-hexame-thoxy flavone, other name Chuan Ting, also known as tangerine flavone A poly (methoxy) flavonoids extracted from the peel of oranges Citrus reticulaia Blanco of the oranges of rutfamily. In recent years, it has been studied that it has many biological activities, such as anti-inflammatory, antioxidant, anti-tumor and neuroprotection, and its effect may be associated with the inhibition of the activity of transcription factors such as NF-kB and activator protein -1 (AP-1). So far, the pharmacological effects and anti inflammatory mechanisms of the pericarin have not been elucidated, but it is also necessary to further evaluate the therapeutic effect of the drug as a treatment for the liver injury of sepsis. The animal model of lipopolysaccharide induced liver injury in mice was used to observe the changes in the mortality of mice after the treatment of septic liver injury, the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), the changes of TNF- a, IL-1 beta and IL-6 in serum and liver tissues, and the extraction of Kupffer cells and detection of Kupffer cells. The changes in the content of I NOS and COX-2 in the inflammatory mediators were measured, and the changes of NF- kappa B, MAPK (ERK, JNK and p38MAPK) and Nrf2-HO-1 signal transduction pathway were detected. The purpose of this study was to clarify the molecular mechanism of the treatment of liver injury in sepsis, and to provide a new research idea for the prevention and treatment of liver injury in sepsis. Objective: To observe the protective effect of peptide on sepsis liver injury in mice. Methods: a mouse model of sepsis liver injury was established by intraperitoneal injection of endotoxin. 75 adult C57BL/6 mice were randomly divided into five groups: normal control group (15, phosphate buffer solution), and LPS model group (15 mice, LPS 10mg /kg), low dose group (15, LPS10mg/kg and 50mg/kg), medium dose group (15, LPS 10mg/kg and LPS10mg/kg), high dose group (15, LPS 10mg/kg, and citpericin 200mg/kg). Each group was killed at different time points (6h, 12h, 24h), respectively, to kill 5 mice, respectively, to collect blood and collect blood. The pathological changes of liver tissue were observed by.HE staining, and the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) were measured in the serum and serum and liver tissue, and the content of TNF- alpha, IL-1 beta and IL-6 in the serum and liver tissues was measured. In addition, 50 mice were repeated and observed and compared for 72 hours after injection. Results: compared with the normal control group, the indexes of the model group and the drug intervention group were significantly changed, which showed that the model was successfully constructed. (1) after LPS injection of 2h, the model group and the drug intervention group were all depressed, touched, shortness of breath, hypothermia, no water and so on, and NOB dry. The spirit and state of the pretreated mice were relatively good. (2) after 24h after LPS injection, there were obvious pathological changes in the liver of mice, tissue cell swelling, necrosis, congestion and inflammatory cell infiltration, but the tissue injury in the NOB intervention group was significantly relieved; (3) the level of ALT, AST and TBil in the serum of the model group was significantly higher than that in the normal control group, and the above finger in the NOB intervention group was marked. Significantly decreased (P0.05 or P0.01); (4) the levels of inflammatory factors TNF- a, IL-1 beta and IL-6 in the serum and liver homogenate of the model group were significantly increased, and the above indexes in the NOB intervention group were significantly decreased (P0.05 or P0.01). (5) the normal control group, the model group and the NOB intervention group found that the survival rate of the normal control group was 100%, the model group mice 72h raw. The survival rate was 0%. The NOB intervention group could effectively improve the 72h survival rate of sepsis mice: the survival rate of 72h in 50mg/kg dose group was 40%, the survival rate of 72h in 100mg/kg dose group was 50%, and 72h survival rate in 200mg/kg dose group was 80%. Inflammatory cells infiltration, reduce the release of liver enzymes, and then play a protective role in sepsis liver injury mice, and ultimately improve the survival rate of mice. Second: the second part: the effect of citrine on the IkB/NF-kB signaling pathway of Kupffer cells activated in mice: by observing the IkB/NF-kB signal of Kupffer cells activated by LPS in mice. The molecular mechanism of the protective effect of Chen piperine in the liver injury of sepsis was explained. Methods: Kupffer cells were separated by collagenase digestion, density gradient centrifugation and selective adherence method, and inoculated into six hole plates and divided into five groups randomly: normal control group (phosphate buffer solution), LPS model group (LPS 10 g/ml), and low Chen piperinin The dose group (LPS 10 mu g/ml and Sichuan Chen piperine 10 u M), the middle dose group (LPS 10 mu g/ml and citpericin 20 micron), the high dose group (LPS 10 mu g/ml and citpericin 40 M). After the drug stimulation, the cell culture and the cell culture supernatant were collected in 1H and 12h, respectively. Alpha, IL-1 beta, IL-6 levels, and Kupffer cells p-IkB, IkB, p-p65, p65 protein changes when 1H was detected by Western blotting. After 1h, the proportion of p-IkB/IkB, p-p65/p65 protein in Kupffer cells increased significantly (P0.05 or P0.01), and the DNA binding activity of NF-kB p65 in the nucleus increased significantly (P0.05 or P0.01) after LPS stimulation of 1H (P0.05 or P0.01). Conclusion: the protective effect of Chen piperin on hepatic injury of sepsis may be related to inhibiting the overactivation of IkB/NF-kB signaling pathway in Kupffer cells and reducing the protein expression of related inflammatory factors. Third part: the effect of the effect of Chen piperin on the MAPK and Nrf2-HO-1 signaling pathway of LPS activated Kupffer cells in mice: by observing the effects of Chen piperine on LP The effect of S activated Kupffer cells MAPK (ERK, JNK and p38MAPK) and Nrf2-HO-1 signaling pathway to explore the molecular mechanism of the protective effect of citalinin on the liver injury of sepsis. Methods: the isolated collagenase digestion, density gradient centrifugation and selective adherence method were used to separate Kupffer cells and be inoculated into five groups randomly. Group (phosphate buffer), LPS model group (LPS 10 mu g/ml), low dose group of Chen piperin (LPS 10 mu g/ml and 10 mu of Chen piperin), middle dose group of Chen piperin (LPS 10 mu g/ml and citpericin 20 micron), high dose group of Chen piperin (LPS 10 mu g/ml and Chen piperine 40 mu M). P-ERK, p-JNK, p-p38MAPK, Nrf2, HO-1, I NOS, COX-2 expression protein changes. Results: LPS stimulation in vitro Kupffer cell 1H, p-ERK, the expression was significantly higher than the normal control group. The expression of -1 and the expression of Nrf2 protein in the nucleus was slightly higher than that in the normal control group, but the above indexes were significantly increased (P0.05 or P0.01) after different doses of the dried tangerinin. After LPS stimulation of 12h, the expression of I NOS and COX-2 protein in the cells was significantly higher than that in the normal control group (P0.05 or P0.01), and the above indexes were significantly decreased after the different doses of the dried tangerinin (P0) (P0). .05 or P0.01) conclusion: the protective effect of Chen piperin on liver injury in sepsis may be related to the inhibition of the overactivation of MAPK (ERK, JNK and p38 MAPK) signaling pathways in Kupffer cells, reducing the expression of I NOS and COX-2 in inflammatory mediators and activating the Nrf2-HO-1 antioxidant pathway.

【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R459.7

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