TLR2和TLR4在抗病毒天然免疫应答中的新作用

越来越多的研究表明TLR2和TLR4参与宿主细胞抗病毒感染的天然免疫应答,为了进一步了解TLR2和TLR4的新作用,本文重点归纳TLR2和TLR4的细胞定位、活化的信号途径和介导的细胞因子反应及其共受体,详细总结TLR2和TLR4识别的病毒及介导的抗病毒天然免疫应答,指出TLR2与TLR4互作的新方式,旨在为宿主抗病毒感染的新机制提供新思路。     

TLR介导的信号通路在肝纤维化中的作用

Toll样受体(Toll - like receptor,TLR)是在天然免疫与获得性免疫应答中发挥重要作用的模式识别受体(Pattern recognition receptors,PRRs).TLR识别来源于病原体或机体损伤产生的“危险信号”,介导多种炎症因子释放,激发机体对病原体的免疫反应,启动固有免疫并进一步活...     

血红素加氧酶-1对急性重症胰腺炎相关肺损伤TLR4/NF-κB通路的影响

目的:探讨血红素加氧酶-1(HO-1)对急性重症胰腺炎相关肺损伤(PALI)Toll样受体-4(TLR4)/核因子-κB(NF-κB)信号传导通路的影响。方法:32只SD大鼠随机分为Sham组、PALI组、HO-1促进剂组、HO-1抑制剂组,每组8只。PALI组经胆胰管注入牛磺胆酸钠制备急性重症胰腺炎(ANP)动物模型。Sham组胆胰管内不注入牛磺胆酸钠,其余操作同PALI组。HO-1促进剂组于造模后30 min经腹腔注射牛血晶素75μg/kg;HO-1抑制剂组于造模后30 min经腹腔注射锌-原卟啉20μmol/kg。PALI组和Sham组均于造模后30 min经腹腔注射等量生理盐水。各组大鼠术后24 h,进行肺损伤学评分,统计肺湿/干重比值。检测大鼠术后24 h血清淀粉酶、TNF-α、IL-6、NGAL水平。检测大鼠术后24 h肺组织中TLR4、NF-κB p65蛋白表达。结果:PALI组肺损伤学评分、肺湿/干重比值、淀粉酶、TNF-α、IL-6、NGAL、TLR4、NF-κB p65明显高于Sham组;HO-1促进剂组肺损伤学评分、肺湿/干重比值、淀粉酶、TNF-α、IL-6、NGAL、TLR4、NF-κB p65明显低于PALI组;HO-1抑制剂组肺损伤学评分、肺湿/干重比值、淀粉酶、TNF-α、IL-6、NGAL、TLR4、NF-κBp65明显高于PALI组;差异均有统计学意义(P<0.05)。结论:HO-1能够通过抑制TLR4/NF-κB信号通路的激活,下调TNF-α、IL-6、NGAL等炎症因子的释放,从而发挥减轻急性重症胰腺炎相关肺损伤的作用。     

基于TLR3/TRIF通路探讨栀子苷抗流感病毒引起的病毒性肺炎的实验研究

中药在预防和治疗流感病毒方面具有独特的优势,栀子苷具有抗炎抗病毒作用,但栀子苷保护流感病毒引起的肺损伤的作用机制尚不明确。为了基于Toll样受体3(Toll-like receptor 3,TLR3)/β干扰素TIR结构域衔接蛋白(TIR-domain-containing adaptor inducing interferon-β,TRIF)信号传导途径探讨栀子苷对流感病毒诱导的肺损伤的调节作用,本研究按照随机数字表法将108只小鼠分为空白对照组、模型组、阳性对照组(50mg/kg利巴韦林)、低剂量栀子苷组(5mg/kg栀子苷)、中剂量栀子苷组(10mg/kg栀子苷)、高剂量栀子苷组(20mg/kg栀子苷)、TLR3激动剂组、TLR3激动剂+阳性药物组、TLR3激动剂+高剂量栀子苷组。采用流感病毒亚甲型鼠肺适应株A/FM/1/47(H1N1)建立流感病毒性肺炎小鼠模型,摘取肺组织,测定小鼠肺指数,HE染色观察肺组织病理学变化,酶联免疫法检测肺组织白介素-6(Interleukin-6,IL-6)、肿瘤坏死因子-α(Tumor necrosis factor-α,TNF-α)和干扰素-...     

急性出血坏死性胰腺炎肝损伤中TLR2, 4mRNA和蛋白的表达

目的:观察急性出血坏死性胰腺炎肝损伤中TLR-2、TLR4的表达水平,分析TLR2和TLR4在AHNP肝损伤中的表达意义。方法:48只成年Wistar大鼠作为实验动物,随机分为对照组和造模组各24只,造模组利用牛磺胆酸钠建立AHNP模型,在造模后3 h、12 h以及24 h时,每组分别各取8只大鼠,应用RT-PCR法检测TLR2、TLR4mRNA表达水平,应用Western blot检测肝脏组织中TLR2、TLR4蛋白表达水平。结果:造模后,造模组TLR2mRNA、TLR4mRNA、TLR2蛋白、TLR4蛋白显著升高,且在造模后12 h出现峰值,与同时段对照组相比差异显著(P0.01)。结论:急性出血坏死性胰腺炎肝损伤组织中TLR2、TLR4mRNA和蛋白表达水平异常升高,TLR2、TLR4可能参与了急性出血坏死性胰腺炎肝损伤发生发展过程。     

蛇毒与急性肺损伤的研究进展

据有关部门统计,全世界蛇类有2700多种,其中毒蛇有600多种。我国的蛇类有200多种,其中毒蛇类有50多种,包括10多种剧毒蛇如眼镜王蛇、金环蛇、眼镜蛇、五步蛇、银环蛇、蝰蛇、蝮蛇、竹叶青、烙铁头、海蛇等,咬伤人后能致人于死亡。在我国,蛇伤病人较常见,     

急性肺损伤中IL-6/GP130/STAT3信号通路的研究进展

正急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)是由多种效应细胞、炎性介质共同参与,并呈现出级联放大的继发性弥漫性肺实质损伤和瀑布样炎症继发性损伤。据统计[1],ALI/ARDS的病死率在26%~35%,其致病环节众多、发病机制复杂、病因多元化,已成为临床危重病学研究的难点和热点问题。近年来,IL-6/GP130/STAT3信号通路靶向治疗急性肺损伤已成为了研究热点,为急性肺损伤患者提供了一种新的治疗方式,也为急性肺损伤患者带来新的希望。本文就IL-6/GP130/STAT3信号通路在急性肺损伤治     

内质网应激与急性肺损伤的研究进展

正内质网应激(endoplasmic reticulum stress,ERs)表现为内质网腔内错误折叠与未折叠蛋白聚集以及钙离子平衡紊乱,可激活未折叠蛋白反应、内质网超负荷反应和caspase-12介导的凋亡通路等信号途径,既能诱导葡萄糖调节蛋白78(glucose regulated protein 78kD,GRP78)、GRP94等内质网分子伴侣表达而产生保护效应,亦能独立诱导细胞凋亡。内质网应激直接影响应激细胞的转归,如适应、损伤或凋亡。急性肺损伤(acute lung injury,ALI)是在严重感染、休克、创伤及烧伤等非心源性疾病过程中,肺毛细血管内皮细胞和肺     

H_2S与急性肺损伤研究进展

<正>急性肺损伤是一种过度炎症反应,它是在感染、创伤等过程中导致的一种过度炎性反应,严重时则被称为急性呼吸窘迫综合征。多年来,急性肺损伤一直是临床常见的严重疾病,急性肺损伤的发病机制也未完全阐明。大量研究证明,继NO和CO之后的第3种信号分子H2S是重要的信使分子,并具有血管功能调节的作用。还有研究证明,H2S具有多方面的生物学作用,如参与低氧性肺动脉高压和感染性休克以及减轻兴奋性氨基酸对神经元的毒性作用等。内源性     

体外模拟脑缺血再灌注条件下BV-2细胞TLR4信号途径对TLR2表达的影响

研究证实,TLR4和TLR2有可能作为重要炎性受体介导脑缺血再灌注炎性损伤.然而目前还不清楚在此过程中TLR2和TLR4受体之间是否存在着交叉对话可能.本研究首先利用针对TLR4基因的RNA干扰技术阻断体外模拟脑I/R条件下BV-2细胞TLR4信号传导途径,观察此时TLR2受体表达变化,初步探讨TLR4信号途径对TLR2表达的影响.然后利用NF-κB抑制剂PDTC阻断NF-κB活性来观察体外模拟脑I/R条件下BV-2细胞TLR2和TLR4受体表达变化,进一步阐明NF-κB在TLR2和TLR4交叉对话中的作用.结果表明：（1）体外模拟脑I/R条件下阻断BV-2细胞TLR4信号传导途径可以明显抑制TLR2和NF-κB表达的上调;（2）PDTC预处理后在体外模拟脑I/R条件下BV-2细胞TLR2和TLR4的表达均下调.结果提示,脑I/R损伤中TLR4受体激活后有可能通过NF-κB的介导,进一步影响TLR2的表达,从而导致炎症反应的链式放大,两者协同加重了脑损伤的过程.     

TLR-2/TLR-4 TREM-1 Signaling Pathway Is Dispensable in Inflammatory Myeloid Cells during Sterile Kidney Injury

Inflammatory macrophages are abundant in kidney disease, stimulating repair, or driving chronic inflammation and fibrosis. Damage associated molecules (DAMPs), released from injured cells engage pattern recognition receptors (PRRs) on macrophages, contributing to activation. Understanding mechanisms of macrophage activation during kidney injury may lead to strategies to alleviate chronic disease. We identified Triggering-Receptor-in-Myeloid-cells (TREM)-1, a regulator of TLR signaling, as highly upregulated in kidney inflammatory macrophages and tested the roles of these receptors in macrophage activation and kidney disease. Kidney DAMPs activated macrophages in vitro, independently of TREM-1, but partially dependent on TLR-2/−4, MyD88. In two models of progressive interstitial kidney disease, TREM-1 blockade had no impact on disease or macrophage activation in vivo, but TLR-2/−4, or MyD88 deficiency was anti-inflammatory and anti-fibrotic. When MyD88 was mutated only in the myeloid lineage, however, there was no bearing on macrophage activation or disease progression. Instead, TLR-2/−4 or MyD88 deficiency reduced activation of mesenchyme lineage cells resulting in reduced inflammation and fibrosis, indicating that these pathways play dominant roles in activation of myofibroblasts but not macrophages. To conclude, TREM-1, TLR2/4 and MyD88 signaling pathways are redundant in myeloid cell activation in kidney injury, but the latter appear to regulate activation of mesenchymal cells.     

亲环蛋白在病毒感染中的作用

亲环蛋白家族是一类具有肽酰-脯氨酰顺反异构酶活性的蛋白.亲环蛋白不仅具有帮助蛋白质组装和折叠、参与调节细胞内信号转导通路等多种生物学功能,还在病毒感染及病毒的复制周期中起到重要作用.本文就亲环蛋白在病毒感染过程中的具体分子机制进行综述,旨在更深入的阐明病毒的感染过程并为寻找潜在的抗病毒药物靶标提供新的理论依据及思路.     

Expression of Suppressor of Cytokine Signaling 1 (SOCS1) Impairs Viral Clearance and Exacerbates Lung Injury during Influenza Infection

Suppressor of cytokine signaling (SOCS) proteins are inducible feedback inhibitors of cytokine signaling. SOCS1^−/− mice die within three weeks postnatally due to IFN-γ-induced hyperinflammation. Since it is well established that IFN-γ is dispensable for protection against influenza infection, we generated SOCS1^−/−IFN-γ^−/− mice to determine whether SOCS1 regulates antiviral immunity in vivo. Here we show that SOCS1^−/−IFN-γ^−/− mice exhibited significantly enhanced resistance to influenza infection, as evidenced by improved viral clearance, attenuated acute lung damage, and consequently increased survival rates compared to either IFN-γ^−/− or WT animals. Enhanced viral clearance in SOCS1^−/−IFN-γ^−/− mice coincided with a rapid onset of adaptive immune responses during acute infection, while their reduced lung injury was associated with decreased inflammatory cell infiltration at the resolution phase of infection. We further determined the contribution of SOCS1-deficient T cells to antiviral immunity. Anti-CD4 antibody treatment of SOCS1^−/−IFN-γ^−/− mice had no significant effect on their enhanced resistance to influenza infection, while CD8⁺ splenocytes from SOCS1^−/−IFN-γ^−/− mice were sufficient to rescue RAG1^−/− animals from an otherwise lethal infection. Surprisingly, despite their markedly reduced viral burdens, RAG1^−/− mice reconstituted with SOCS1^−/−IFN-γ^−/− adaptive immune cells failed to ameliorate influenza-induced lung injury. In conclusion, in the absence of IFN-γ, the cytoplasmic protein SOCS1 not only inhibits adaptive antiviral immune responses but also exacerbates inflammatory lung damage. Importantly, these detrimental effects of SOCS1 are conveyed through discrete cell populations. Specifically, while SOCS1 expression in adaptive immune cells is sufficient to inhibit antiviral immunity, SOCS1 in innate/stromal cells is responsible for aggravated lung injury.     

microRNA及Wnt 信号通路在急性淋巴细胞白血病中的作用研究进展

micro RNAs(mi RNAs)是一种内源性的基因调控元件,参与细胞增殖、分化、凋亡等多种重要生物学过程。在许多实体瘤和血液系统恶性肿瘤中均存在mi RNA异常表达,说明mi RNA可能参与肿瘤的发生及发展。Wnt通路是一条经典的信号通路,其异常激活与多种实体瘤和血液系统恶性肿瘤的发生发展密切相关。急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)是一种常见的成人血液系统恶性肿瘤,现已发现多种mi RNA在ALL中异常表达,并与发病、治疗效果及预后有关。在ALL中可见Wnt信号通路的异常激活及通路抑制剂的异常失活,并且这些变化与ALL的预后密切相关。本文就mi RNAs和Wnt信号通路在急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)中的作用相关研究进展作一综述,以提供靶向治疗ALL的新思路。     

Effects of the Notch Signaling Pathway on Secondary Brain Changes Caused by Spinal Cord Injury in Mice

Neurochemical Research - Spinal cord injury (SCI) can cause secondary brain changes, leading to hypomyelination in the dorsolateral prefrontal cortex (dlPFC). Some studies have shown that notch...     

褪黑素通过激活SIRT1信号通路发挥抗肺缺血再灌注损伤作用

目的:研究褪黑素(Melatonin,Mel)在肺缺血再灌注损伤中的作用,明确沉默信息调控因子1(Silent information regulator 1,SIRT1)信号通路在这一过程中的关键作用。方法:建立大鼠肺缺血再灌注损伤(IR)模型,实验分为Control、IR、IR+10 mg/Kg Mel、IR+20 mg/Kg Mel、IR+30 mg/Kg Mel五组,通过检测支气管肺泡灌洗液中白细胞数目、蛋白含量和肺组织中丙二醛(MDA)水平、干湿重比等指标明确肺组织损伤程度,Western blot检测SIRT1通路相关分子及凋亡相关蛋白的表达水平,研究其作用机制。结果:与IR组相比,Mel处理显著降低了支气管肺泡灌洗液中白细胞数量、蛋白含量和肺组织MDA含量、干湿重比(P0.05);Mel还显著上调了SIRT1表达,降低了Ac-FOXO1表达(P0.05);此外,Mel显著提高了抗凋亡蛋白Bcl-2表达,下调了凋亡蛋白Bax表达(P0.05)。结论:Mel具有明确的抗肺缺血再灌注损伤的作用,SIRT1信号通路在该过程中可能扮演重要角色。     

N-Acetyl-Heparin Attenuates Acute Lung Injury Caused by Acid Aspiration Mainly by Antagonizing Histones in Mice

Acute lung injury (ALI) is the leading cause of death in intensive care units. Extracellular histones have recently been recognized to be pivotal inflammatory mediators. Heparin and its derivatives can bind histones through electrostatic interaction. The purpose of this study was to investigate 1) the role of extracellular histones in the pathogenesis of ALI caused by acid aspiration and 2) whether N-acetyl-heparin (NAH) provides more protection than heparin against histones at the high dose. ALI was induced in mice via intratracheal instillation of hydrochloric acid (HCl). Lethality rate, blood gas, myeloperoxidase (MPO) activity, lung edema and pathological changes were used to evaluate the degree of ALI. Heparin/NAH was administered intraperitoneally, twice a day, for 3 days or until death. Acid aspiration caused an obvious increase in extracellular histones. A significant correlation existed between the concentration of HCl aspirated and the circulating histones. Heparin/NAH (10 mg/kg) improved the lethality rate, blood gas, MPO activity, lung edema and pathological score. At a dose of 20 mg/kg, NAH still provided protection, however heparin tended to aggravate the injury due to hemorrhagic complications. The specific interaction between heparin and histones was verified by the binding assay. In summary, high levels of extracellular histones can be pathogenic in ALI caused by acid aspiration. By neutralizing extracellular histones, heparin/NAH can offer similar protection at the moderate doses. At the high dose, NAH provides better protection than heparin.     

TLR4-Nrf2/HO-1信号通路在小鼠机械通气所致肺损伤的作用研究

目的:机械通气作为一重要措施,拯救呼吸衰竭患者的生命,有致肺血管炎症及渗透增加等病变的可能,即VILI。本研究旨在明确VILI是否受潮气量、Toll样受体4(Toll-like receptor-4,TLR4)基因敲除及核因子-E2相关受体2/血红素氧化酶-1(Nuclear factor-erythroid 2 related factor2/heme oxygenase 1,Nrf2/HO-1)表达的激活关联是否存在。方法:TLR4基因缺失和野生型(WT)小鼠分别分为对照(CON),低潮气量(low tidal volume,LTV)和高潮气量(high tidal volume,HTV)组。给小鼠禁食、禁水12小时后,麻醉小鼠,做气管切开,将气管导管经口插入,通气4小时,呼气末正压(PEEP)2 cm H2O,R:100次/分钟,吸呼比1:2;CON组仅气管插管。小鼠处死,测湿/干重比(W/D)。肺组织依次:HE染色组织学评价;评价肺损伤评分;测定肺炎症因子表达:肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)及白介素-1β(interleukin-1β,IL-1β);免疫组化及免疫印迹法,测Nrf2蛋白值;测HO-1蛋白值。结果:在WT+HTV组,Nrf2和HO-1的表达比较WT+LTV组明显升高,但受到TLR4基因敲除的调节,相应的TLR4基因敲除组升高更明显。肺损伤评分、湿/干比在WT+HTV组增加,相应的TLR4基因敲除组升高更显著。结论:HTV通气可致小鼠VILI。VILI小鼠肺中的Nrf2/HO-1表达升高,TLR4基因缺失可以升高Nrf2/HO-1表达,保护肺组织,减轻VILI。