清道夫受體A調(diào)控中性粒細(xì)胞誘導(dǎo)補(bǔ)體活化在暴發(fā)性肝炎發(fā)生發(fā)展中的作用研究
發(fā)布時間：2018-08-31 18:44
【摘要】：暴發(fā)性肝炎(Fulminant hepatitis,FH)是一種罕見的急性疾病,伴隨肝功能急速惡化,肝細(xì)胞大面積壞死甚至肝性腦病等特征。盡管近年來對FH的治療方法有所進(jìn)步,但其仍可導(dǎo)致較高的死亡率。臨床證據(jù)表明,在人類FH進(jìn)程中纖維蛋白大量沉積和微脈管血栓形成是造成肝細(xì)胞損傷的重要原因。此外,免疫細(xì)胞的激活和后續(xù)產(chǎn)生的促炎細(xì)胞因子(例如TNF-α,IL-1β,IL-6和IFN-γ)也在促進(jìn)FH疾病進(jìn)展中發(fā)揮重要作用。因此,探討FH的免疫學(xué)發(fā)病機(jī)制將為研究FH更普遍和有效的治療提供思路。清道夫受體A(ScavengerReceptor A,SRA)主要表達(dá)在髓系細(xì)胞表面,如巨噬細(xì)胞和樹突狀細(xì)胞。Ozment等發(fā)現(xiàn)SRA也能表達(dá)在循環(huán)和骨髓中的中性粒細(xì)胞表面,并在受到TLR2激動劑刺激后表達(dá)上調(diào)。SRA作為天然免疫中的模式識別受體(pattern recognition receptor,PRR),能夠識別廣泛的“自己”和“非己”配體,在機(jī)體抵御病原微生物的侵入和維持免疫穩(wěn)態(tài)中發(fā)揮重要作用。越來越多的研究表明,SRA還可作為免疫調(diào)控分子參與多種炎癥性疾病的發(fā)病進(jìn)程,其免疫調(diào)控作用可能與其內(nèi)吞作用相互獨(dú)立。我們發(fā)現(xiàn)SRA在HBV感染的暴發(fā)型肝炎病人的肝組織中高表達(dá)。然而,目前尚未見SRA在暴發(fā)性肝炎中的免疫調(diào)節(jié)作用研究。鼠肝炎病毒(Mouse hepatitis virus,MHV)是單正鏈RNA病毒,可用于構(gòu)建敏感小鼠的肝炎、腸炎或腦炎模型。Balb/c和C57/BL6小鼠腹腔感染嗜肝性MHV病毒(如MHV-3和MHV-A59)后可在肝血竇形成血栓,肝細(xì)胞大量壞死,因此可以作為研究人類FH的有效模型。與野生型(wild-type,WT)小鼠相比,SRA-/-小鼠對MHV-A59誘導(dǎo)的暴發(fā)性肝炎耐受,并伴隨著肝臟炎癥反應(yīng)的減輕和血清中纖維介素(fibrinogen-like protein 2,Fgl2)下降;使用C5aR拮抗劑后,小鼠肝損傷明顯減輕,并且WT小鼠與SRA-/-小鼠肝臟炎癥反應(yīng)和肝損傷差異消失,這表明在FH進(jìn)程中SRA通過上調(diào)C5a表達(dá)加劇MHV的炎癥效應(yīng)和肝損傷。研究發(fā)現(xiàn),中性粒細(xì)胞表達(dá)的SRA調(diào)控WT小鼠與SRA-/-小鼠病毒感染所致肝損傷的差異;SRA通過促進(jìn)MHV-A59刺激中性粒細(xì)胞內(nèi)TAK1磷酸化上調(diào)ERK的激活進(jìn)而影響中性粒細(xì)胞胞外誘捕網(wǎng)(neutrophil extracellular traps,NETs)的形成和中性粒細(xì)胞彈性蛋白酶(neutrophil elastase,NE)的釋放,隨后,NE誘導(dǎo)C5裂解為C5a發(fā)揮促炎效應(yīng);小鼠體內(nèi)使用NE的抑制劑西維來司鈉后,病毒感染W(wǎng)T小鼠和SRA--小鼠所致肝損傷和C5a的表達(dá)量無顯著性差異;并且我們發(fā)現(xiàn)阻斷SRA可以減輕MHV-A59所致的肝損傷。綜上,SRA調(diào)控MHV-A59誘導(dǎo)的中性粒細(xì)胞NET形成,進(jìn)而促進(jìn)C5a產(chǎn)生和后續(xù)的肝損傷。抑制SRA可能為FH免疫學(xué)治療提供新的策略。
[Abstract]:Fulminant hepatitis (Fulminant hepatitis,FH) is a rare acute disease characterized by rapid deterioration of liver function, massive necrosis of hepatocytes and even hepatic encephalopathy. Despite advances in treatment of FH in recent years, it can lead to higher mortality. Clinical evidence shows that fibrin deposition and microvascular thrombosis are important causes of hepatocyte injury in human FH process. In addition, the activation of immune cells and the subsequent production of pro-inflammatory cytokines (such as TNF- 偽, IL-1 尾, IL-6 and IFN- 緯) also play an important role in promoting the progression of FH. Therefore, the study of immunological pathogenesis of FH will provide ideas for the study of more general and effective treatment of FH. Scavenger receptor A (ScavengerReceptor Agna was mainly expressed on the surface of myeloid cells, such as macrophages and dendritic cells. Ozment found that SRA could also be expressed on the surface of neutrophils in circulation and bone marrow. After stimulation with TLR2 agonists, the expression of. SRA was up-regulated as a pattern recognition receptor (pattern recognition receptor,PRR) in innate immunity, which could recognize a wide range of "self" and "non-hexane" ligands. It plays an important role in resisting the invasion of pathogenic microorganisms and maintaining immune homeostasis. More and more studies have shown that SRA can also participate in the pathogenesis of various inflammatory diseases as an immunomodulator, and its immune regulation may be independent of its endocytosis. We found high expression of SRA in liver tissues of HBV infected fulminant hepatitis patients. However, the immunomodulatory effect of SRA in fulminant hepatitis has not been studied. Murine hepatitis virus (Mouse hepatitis virus,MHV) is a single positive strand RNA virus. It can be used to construct hepatitis, enteritis or encephalitis model. Balb / c and C57/BL6 mice are infected with hepatophilic MHV virus (such as MHV-3 and MHV-A59). Therefore, it can be used as an effective model for the study of human FH. Compared with the wild-type (wild-type,WT) mice, SRA-r- mice were resistant to fulminant hepatitis induced by MHV-A59, accompanied by the reduction of inflammatory reaction in the liver and the decrease of fibrinogen-like protein _ 2 Fgl2 in serum, and the liver injury was significantly alleviated by the use of C5aR antagonist. Moreover, the difference between WT mice and SRA-/- mice in liver inflammation and liver injury disappeared, which indicated that SRA increased the inflammatory effect and liver injury of MHV by up-regulating C5a expression during the FH process. The study found that, The difference of SRA expression of neutrophils in regulating liver injury induced by virus infection in WT mice and SRA-/- mice. SRA promotes MHV-A59 stimulation of TAK1 phosphorylation in neutrophilic granulocytes to up-regulate the activation of ERK, thereby affecting the extracellular neutrophil trapping network (neutrophil extracellular The formation of traps,NETs and the release of neutrophil elastase (neutrophil elastase,NE). Ne-induced C _ 5 cleavage to C _ 5a played a pro-inflammatory effect, and there was no significant difference in liver injury and C5a expression between WT mice and SRA-- mice after the use of sivelestat sodium, an inhibitor of NE, in vivo. And we found that blocking SRA can alleviate liver injury induced by MHV-A59. SRA regulates neutrophil NET formation induced by MHV-A59 and promotes C5a production and subsequent liver injury. Inhibition of SRA may provide a new strategy for immunotherapy of FH.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R575.1
本文編號：2215845
[Abstract]:Fulminant hepatitis (Fulminant hepatitis,FH) is a rare acute disease characterized by rapid deterioration of liver function, massive necrosis of hepatocytes and even hepatic encephalopathy. Despite advances in treatment of FH in recent years, it can lead to higher mortality. Clinical evidence shows that fibrin deposition and microvascular thrombosis are important causes of hepatocyte injury in human FH process. In addition, the activation of immune cells and the subsequent production of pro-inflammatory cytokines (such as TNF- 偽, IL-1 尾, IL-6 and IFN- 緯) also play an important role in promoting the progression of FH. Therefore, the study of immunological pathogenesis of FH will provide ideas for the study of more general and effective treatment of FH. Scavenger receptor A (ScavengerReceptor Agna was mainly expressed on the surface of myeloid cells, such as macrophages and dendritic cells. Ozment found that SRA could also be expressed on the surface of neutrophils in circulation and bone marrow. After stimulation with TLR2 agonists, the expression of. SRA was up-regulated as a pattern recognition receptor (pattern recognition receptor,PRR) in innate immunity, which could recognize a wide range of "self" and "non-hexane" ligands. It plays an important role in resisting the invasion of pathogenic microorganisms and maintaining immune homeostasis. More and more studies have shown that SRA can also participate in the pathogenesis of various inflammatory diseases as an immunomodulator, and its immune regulation may be independent of its endocytosis. We found high expression of SRA in liver tissues of HBV infected fulminant hepatitis patients. However, the immunomodulatory effect of SRA in fulminant hepatitis has not been studied. Murine hepatitis virus (Mouse hepatitis virus,MHV) is a single positive strand RNA virus. It can be used to construct hepatitis, enteritis or encephalitis model. Balb / c and C57/BL6 mice are infected with hepatophilic MHV virus (such as MHV-3 and MHV-A59). Therefore, it can be used as an effective model for the study of human FH. Compared with the wild-type (wild-type,WT) mice, SRA-r- mice were resistant to fulminant hepatitis induced by MHV-A59, accompanied by the reduction of inflammatory reaction in the liver and the decrease of fibrinogen-like protein _ 2 Fgl2 in serum, and the liver injury was significantly alleviated by the use of C5aR antagonist. Moreover, the difference between WT mice and SRA-/- mice in liver inflammation and liver injury disappeared, which indicated that SRA increased the inflammatory effect and liver injury of MHV by up-regulating C5a expression during the FH process. The study found that, The difference of SRA expression of neutrophils in regulating liver injury induced by virus infection in WT mice and SRA-/- mice. SRA promotes MHV-A59 stimulation of TAK1 phosphorylation in neutrophilic granulocytes to up-regulate the activation of ERK, thereby affecting the extracellular neutrophil trapping network (neutrophil extracellular The formation of traps,NETs and the release of neutrophil elastase (neutrophil elastase,NE). Ne-induced C _ 5 cleavage to C _ 5a played a pro-inflammatory effect, and there was no significant difference in liver injury and C5a expression between WT mice and SRA-- mice after the use of sivelestat sodium, an inhibitor of NE, in vivo. And we found that blocking SRA can alleviate liver injury induced by MHV-A59. SRA regulates neutrophil NET formation induced by MHV-A59 and promotes C5a production and subsequent liver injury. Inhibition of SRA may provide a new strategy for immunotherapy of FH.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R575.1
【參考文獻(xiàn)】
相關(guān)期刊論文 前2條
1 陳悅,寧琴,王寶菊,張東紳,嚴(yán)福明,孫奕,習(xí)東,嚴(yán)偉明,郝連杰,GLevy,羅小平;重型乙型肝炎患者肝組織中人纖維介素基因的表達(dá)及意義[J];中華醫(yī)學(xué)雜志;2003年06期
2 ;Detection of serum TNF-α,IFN-γ,IL-6 and IL-8 in patients with hepatitis B[J];世界胃腸病學(xué)雜志;1999年01期
，本文編號：2215845
本文鏈接：http://sikaile.net/yixuelunwen/xiaohjib/2215845.html
最近更新
教材專著
