基于TLR4 / NF-κB 信号通路探讨通痹胶囊对胶原诱导型关节炎治疗机制的研究

目的:基于TLR4/NF-κB信号通路研究通痹胶囊对胶原诱导型关节炎(CIA)的治疗机制。方法:48只SD大鼠随机分为对照组、模型组、雷公藤组(0. 01 g/kg)和通痹胶囊低(0. 075 g/kg)、中(0. 150 g/kg)、高(0. 300 g/kg)剂量组,每组8只;使用牛Ⅱ型胶原和完全弗氏佐剂(CFA)建立大鼠CIA模型;采用HE染色观察滑膜组织病理情况,ELISA检测大鼠血清中白介素1β(IL-1β)、白介素6(IL-6)和肿瘤坏死因子α(TNF-α)水平,Western blot检测滑膜组织中Toll样受体4(TLR4)、髓样分化因子88(MyD88)和核因子κB(NF-κB)蛋白表达水平。结果:与正常大鼠相比,模型大鼠关节肿胀度均显著升高,通痹胶囊治疗后关节肿胀度显著降低,模型组滑膜组织增生明显,炎症细胞浸润,关节软骨破坏,通痹胶囊治疗明显改善滑膜组织的增生,降低炎症细胞的浸润;模型组大鼠血清中IL-1β、IL-6、TNF-α水平和滑膜组织中TLR4、MyD88、NF-κB蛋白水平显著升高,通痹胶囊处理后显著降低血清中IL-1β、IL-6、TNF-α水平和滑膜组织中TLR4、MyD88、NF-κB蛋白表达;与通痹胶囊高剂量组相比,TLR4激动剂处理显著提高血清中IL-1β、IL-6、TNF-α水平和滑膜组织中TLR4、MyD88、NF-κB蛋白表达。结论:通痹胶囊可以通过抑制TLR4/NF-κB信号通路,降低炎性反应,显著改善CIA症状。     

贞芪扶正胶囊介导TLR4/MyD88/NF-κB信号通路抑制慢性湿疹小鼠炎症反应

目的 探讨贞芪扶正胶囊对慢性湿疹小鼠炎症反应的抑制作用.方法 SPF级C57BL/6小鼠30只,按随机数字表法随机分为对照组(control组)、模型组(CAD组)与贞芪扶正胶囊组(ZQFZ组).观察各组小鼠双耳肿胀程度、双耳变应评分;HE染色观察病灶处皮肤病理学变化;ELISA法检测血清炎性因子TNF-α、IL-6及IL-1β水平;RT-PCR检测皮肤中TNF-α、IL-6及IL-1β mRNA表达;Western blot检测TLR4、MyD88及NF-κB蛋白表达;RT-PCR检测皮肤中TLR4、MyD88及NF-κB mRNA表达.结果 ZQFZ可以显著改善小鼠双耳肿胀程度,降低小鼠双耳变应评分(P＜0.05);减轻小鼠皮肤炎症浸润并降低血浆及皮肤中TNF-α、IL-6及IL-1β蛋白与mRNA表达(P＜0.05);同时ZQFZ还可显著下调小鼠皮肤组织中TLR4、MyD88、NF-κB蛋白与mRNA表达(P＜0.05).结论 贞芪扶正胶囊可以通过抑制炎性反应达到治疗慢性湿疹作用,其作用机制可能与其调控TLR4/MyD88/NF-κB信号通路有关.     

HSP60及TLR4信号途径在小鼠心脏移植物中的表达及意义

目的:检测HSP60及TLR4信号途径在小鼠心脏移植物中的表达情况,探讨其在心脏移植排斥反应中的作用以及它们之间的关系。方法:建立小鼠颈部心脏移植模型,随机分为2组:对照组(同系移植组),供、受体均为C57BL/6小鼠;实验组(同种异品系移植组),供、受体分别为BALB/c、C57BL/6小鼠。分别于移植后第3d、第7d取小鼠心脏及血液标本,免疫组化及Western blotting检测心脏移植物HSP60、TLR4、MyD88及NF-κB的表达情况,ELISA法检测小鼠血液肿瘤坏死因子-α(TNF-α)、干扰素-γ(IFN-γ)和白细胞介素-12(IL-12)的浓度,病检分析心脏组织形态学改变。结果:实验组心脏移植物HSP60、TLR4、MyD88、NF-κB的表达及TNF-α、IFN-γ、IL-12的浓度明显高于对照组;病理学检查结果显示实验组小鼠在术后第3、7d分别发生轻、重度排斥,对照组无明显排斥现象。结论:心脏移植后HSP60表达增强,可能通过TLR4以MyD88依赖的方式激活TLR4信号途径,从而促进移植排斥反应的发生,调控HSP60及其受体后信号途径可能为抗排斥反应提供新思路。     

Toll样受体4与肿瘤坏死因子α在脑缺血再灌注小鼠顶叶皮质神经元中的表达及意义

目的:探讨Toll样受体4(TLR4)在脑缺血再灌注损伤炎症反应中的作用.方法:采用TLR4抗体封闭TLR4受体,H-E染色观察小鼠顶叶皮质组织病理学改变、免疫印迹法检测顶叶皮质TLR4蛋白表达、RT-PCR检测顶叶皮质TLR4 mRNA表达量、免疫组织化学显色法检测顶叶皮质TNF-α表达情况,TLR4 mRNA表达水平与TNF-α含量相关分析.小鼠随机分为假手术组、缺血再灌注组和TLR4阻断组,各组又分12、 24、 48、 72h 4个时间点组.结果:缺血再灌注组TLR4蛋白、TLR4 mRNA、 TNF-α表达水平明显高于假手术组表达水平,而TLR4阻断组TLR4蛋白、TLR4 mRNA、 TNF-α表达水平明显低于缺血再灌注组,相关分析表明,TLR4 mRNA表达水平与TNF-α含量呈显著正相关.结论:缺血再灌注可激活TLR4,TLR4在脑缺血再灌注损伤中起重要作用;炎性因子TNF-α的产生、分泌可能与TLR4 mRNA表达存在着密切联系.     

MyD88抑制肽对小鼠脑缺血后小胶质细胞极化的影响

目的:研究髓样分化因子88抑制肽(MIP)对小鼠脑缺血后小胶质细胞极化的影响。方法:将30只雄性C57BL/6小鼠分为假手术组(sham)、局灶性脑缺血组(FCI)和给药组(MIP)。用光化学法建立小鼠FCI模型,给药组于造模后第3 d开始给予腹腔注射MIP,每次10 mg/kg,每日一次,连续3 d。采用real time RT-PCR检测损伤区白细胞介素(IL)-1β、IL-4、IL-10、肿瘤坏死因子α(TNF-α)、CD86和CD206 mRNA的表达,用Western Blot检测损伤区局部Toll样受体2(TLR2)、TLR4、髓样分化因子88(MyD88)、诱导型一氧化氮合酶(i NOS)和精氨酸酶-1(Arg-1)蛋白的表达水平,用免疫荧光染色观察损伤区i NOS和Arg-1与F4/80或Iba-1的共标情况。结果:与假手术组相比,FCI组小鼠损伤区MyD88、TLR2和TLR4蛋白的表达水平明显升高。与FCI组相比,MIP给药组小鼠损伤区IL-1β、TNF-ɑ和CD86 mRNA,以及iNOS蛋白的表达量明显下降,而IL-4、IL-10和CD206 mRNA,以及Arg-1蛋白的表达量明显上调。结论:MIP可促使脑缺血模型小鼠损伤区小胶质细胞向M2方向极化。     

TLR4/MyD88/AMPK通路参与调节高脂饮食诱导的肥胖小鼠脂肪组织炎症和细胞凋亡北大核心CSCD

目的:探讨Toll样受体4(TLR4)基因敲除对高脂饮食诱导的肥胖小鼠脂肪组织炎症和细胞凋亡的影响。方法:雄性C57BL/6J和TLR4基因敲除小鼠随机分为正常对照组(NC)、肥胖组(OB)、TLR4基因敲除组(TK)、TLR4基因敲除肥胖组(TO),NC组给予正常饲料喂养,其他组给予高脂饲料喂养。16周后取血检测各组小鼠空腹血糖(FPG)、总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)和游离脂肪酸(FFA)水平;HE染色观察各组小鼠脂肪细胞形态变化;Western blot检测TLR4、磷酸化腺苷酸活化蛋白激酶α(p-AMPKα)、髓样分化因子88(MyD88)、Bax和Bcl-2蛋白表达;ELISA检测小鼠血清单细胞趋化因子-1(MCP-1)、IL-6、TNF-α、IL-10水平。结果:与NC组相比,OB组小鼠脂肪细胞明显增大,FPG、TC、TG、LDL、FFA、MCP-1、IL-6和TNF-α水平明显升高(P<0.01),HDL和IL-10水平明显降低(P<0.01,P<0.05),TLR4、MyD88和Bax表达明显增加(P<0.01),p-AMPKα和Bcl-2表达明显减少(P<0.05);与OB组相比,TO组小鼠上述检测指标表达明显逆转。结论:TLR4基因敲除可通过MyD88依赖的AMPK缓解高脂饮食诱导的肥胖小鼠脂肪组织慢性炎症和细胞凋亡。     

天抗(TK)对脂多糖诱导小鼠炎症模型的抗炎作用及其机制

目的研究天抗(TK)对脂多糖(LPS)诱导的小鼠炎症模型的抗炎作用及机制研究。方法将42只昆明小鼠随机分为正常对照(NC)组、模型对照(LPS)组、地塞米松(DXM)组、天抗低(TK-L)、中(TK-M)和高(TK-H)剂量组(0.2,0.8和3.2 g/kg)。各组分别灌胃给药7 d后,腹腔注射30 mg/kg的LPS诱导小鼠急性炎性模型,6 h后处死小鼠,检测小鼠脾脏指数,ELISA测定小鼠血清中IL-1β、IL-6和TNF-α的表达水平;生化法检测小鼠血清中SOD和MDA的表达;qRT-PCR检测小鼠脾脏TLR4、MyD88、TRAF6、p65、IL-1β、IL-6和TNF-αmRNA的表达水平;Western blot检测小鼠脾脏TLR4、MyD88、TRAF6、p-p65和p65蛋白表达水平。结果与LPS组相比,TK组小鼠的脾脏指数明显降低,血清和脾脏组织中IL-1β、IL-6、TNF-α和MDA水平显著下降,SOD水平明显升高,小鼠脾脏组织的TLR4、MyD88、TRAF6和p-p65等蛋白及mRNA表达水平均明显降低。结论天抗对LPS诱导的小鼠急性炎症模型具有抗炎作用,其作用机制可能是通过TLR4/MyD88/NF-κB(p-65)信号通路抑制炎症因子的释放。     

TLR4基因沉默下调TLR2信号通路在RAW264.7细胞中的抗烟曲霉孢子刺激作用

目的 研究单核巨噬细胞RAW264.7受烟曲霉孢子刺激时,TLR2和TLR4信号通路发挥的作用,以及沉默TLR4基因后,对TLR2信号通路的影响.方法 利用RNAi技术将TLR4-siRNA转染RAW264.7细胞24h后给予烟曲霉孢子刺激12h,将细胞随即分为正常组(N组)、正常+烟曲霉孢子刺激组(N+Af组)、正常+TLR4-siRNA组[TLR4(RNAi)组]、正常+TLR4-siRNA+烟曲霉孢子刺激组[ TLR4(RNAi) +Af组],RT-PCR和Western blot法检测细胞受烟曲霉孢子刺激后TLR2、TLR4、MyD88 mRNA及TNF-α蛋白的表达变化.结果 (1)TLR4基因沉默前:与N组比较,N+Af组TLR2、TLR4、MyD88 mRNA及TNF-α蛋白表达量均显著升高(P＜0.05).(2)TLR4-siRNA( 100nmoL/L)转染RAW264.7细胞,沉默效率达83％.(3)TLR4基因沉默后:与N组比较,TLR4( RNAi)组TLR2、MyD88 mRNA的表达量均显著降低(P＜0.05);与N+Af组比较,TLR4( RNAi)+Af组的TLR2、MyD88 mRNA和TNF-α蛋白的表达量均显著降低(P＜0.05);与TLR4( RNAi)组比较,TLR4(RNAi)+ Af组MyD88 mRNA表达量显著升高(P＜0.05),而TLR2 mRNA及TNF-α蛋白表达量却无显著变化(P＞0.05).结论 RAW264.7细胞受烟曲霉孢子刺激时,TLR2和TLR4信号通路被激活,通过释放促炎细胞因子TNF-α发挥抗烟曲霉孢子刺激作用;当沉默TLR4基因后,TLR2信号通路不能被很好地激活来抵抗烟曲霉孢子对细胞的刺激作用,沉默TLR4基因下调了TLR2信号通路在RAW264.7细胞中的抗烟曲霉孢子刺激作用,可能TLR4较TLR2在抵抗烟曲霉孢子刺激时发挥更重要的作用.     

Toll样受体4/髓样分化蛋白88在早期自然流产母-胎界面的表达

目的:探讨Toll样受体4(TLR4)/髓样分化蛋白88(MyD88)与早期自然流产的相关性。方法:选择30例正常妊娠妇女作为对照组,采用免疫组织化学显色对30例早期自然流产患者(流产组)母-胎界面的蜕膜和绒毛组织中TLR4、MyD88蛋白表达进行定位观察,采用RT-PCR技术对其TLR4和MyD88mRNA表达进行半定量分析。结果:TLR4和MyD88蛋白在流产组和对照组的绒毛及蜕膜组织中均有表达,定位表达于绒毛滋养层细胞、蜕膜细胞的细胞质内,阳性反应强弱不等。RT-PCR半定量分析结果显示,在绒毛组织中,流产组TLR4 mRNA、MyD88 mRNA的表达显著高于对照组;在蜕膜组织中,流产组TLR4 mRNA、MyD88 mRNA的表达显著高于对照组。流产组绒毛和蜕膜组织中TLR4与MyD88的表达均呈正相关。结论:TLR4和MyD88可能参与早期自然流产的病理过程,且TLR4可能通过MyD88信号途径参与早期自然流产的发生。     

大蒜素促进子宫内膜癌荷瘤小鼠肿瘤细胞凋亡

目的探讨大蒜素对子宫内膜癌荷瘤小鼠肿瘤组织的影响及其机制。方法取40只BALB/c裸鼠和人子宫内膜癌细胞系Ishikawa建立子宫内膜癌荷瘤小鼠模型。实验分为模型组(model)和腹腔注入大蒜素(allicin)10、20和40 mg/kg每组2 mL为干预组。测量瘤体积、计算抑瘤率、HE观察病理变化及流式细胞计量术检测细胞凋亡率;实时荧光定量聚合酶链反应(RT-qPCR)检测TLR4和MyD88 mRNA表达;Western blot检测TLR4和MyD88蛋白表达。结果各干预组瘤体积缩小,呈剂量依赖性增加抑瘤率(P0.05);干预组细胞皱缩、核染色质向边缘集中、片状坏死等病理表现,肿瘤组织细胞凋亡率明显降低(P0.05);肿瘤组织TLR4、MyD88 mRNA及蛋白相对表达量降低(P0.05)。结论大蒜素可抑制子宫内膜癌荷瘤小鼠肿瘤增长及促进细胞凋亡。     

Role of the Toll-like receptor pathway in the recognition of orthopedic implant wear-debris particles

The inflammatory response to prosthetic implant-derived wear particles is the primary cause of bone loss and aseptic loosening of implants, but the mechanisms by which macrophages recognize and respond to particles remain unknown. Studies of innate immunity demonstrate that Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS). All TLRs signal through myeloid differentiation factor 88 (MyD88), except TLR3 which signals through TIR domain containing adapter inducing interferon-beta (TRIF), and TLR4 which signals through both MyD88 and TRIF. We hypothesized that wear-debris particles may act as PAMPs/DAMPs and activate macrophages via TLRs. To test this hypothesis, we first demonstrated that inhibition of MyD88 decreases polymethylmethacrylate (PMMA) particle-induced production of TNF-α in RAW 264.7 macrophages. Next we compared particle-induced production of TNF-α among MyD88 knockout (MyD88(-/-)), TRIF knockout (TRIF(-/-)), and wild type (WT) murine macrophages. Relative to WT, disruption of MyD88 signaling diminished, and disruption of TRIF amplified the particle-induced production of TNF-α. Gene expression data indicated that this latter increase in TNF-α was due to a compensatory increase in expression of MyD88 associated components of the TLR pathway. Finally, using an in?vivo model, MyD88(-/-) mice developed less particle-induced osteolysis than WT mice. These results indicate that the response to PMMA particles is partly dependent on MyD88, presumably as part of TLR signaling; MyD88 may represent a therapeutic target for prevention of wear debris-induced periprosthetic osteolysis.     

MyD88 deficiency leads to decreased NK cell gamma interferon production and T cell recruitment during Chlamydia muridarum genital tract infection, but a predominant Th1 response and enhanced monocytic inflammation are associated with infection resolution

We have previously shown that MyD88 knockout (KO) mice exhibit delayed clearance of Chlamydia muridarum genital infection compared to wild-type (WT) mice. A blunted Th1 response and ineffective suppression of the Th2 response were also observed in MyD88 KO mice. The goal of the present study was to investigate specific mechanisms whereby absence of MyD88 leads to these effects and address the compensatory mechanisms in the genital tract that ultimately clear infection in the absence of MyD88. It was observed that NK cells recruited to the genital tract in MyD88 KO mice failed to produce gamma interferon (IFN-γ) mRNA and protein. This defect was associated with decreased local production of interleukin-17 (IL-17), IL-18, and tumor necrosis factor alpha (TNF-α) but normal levels of IL-12p70. Additionally, recruitment of CD4 T cells to the genital tract was reduced in MyD88 KO mice compared to that in WT mice. Although chronic infection in MyD88 KO mice resulted in oviduct pathology comparable to that of WT mice, increased histiocytic inflammation was observed in the uterine horns. This was associated with increased CCL2 levels and recruitment of macrophages as a potential compensatory mechanism. Further deletion of TLR4-TRIF signaling in MyD88 KO mice, using TLR4/MyD88 double-KO mice, did not further compromise host defense against chlamydiae, suggesting that compensatory mechanisms are Toll-like receptor (TLR) independent. Despite some polarization toward a Th2 response, a Th1 response remained predominant in the absence of MyD88, and it provided equivalent protection against a secondary infection as observed in WT mice.     

Toll-like receptor 9 is required for full host resistance to Mycobacterium avium infection but plays no role in induction of Th1 responses

To investigate the role of Toll-like receptor 9 (TLR9) in innate immunity to Mycobacterium avium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control of M. avium infection. However, TLR9 KO or TLR2 KO spleen cells displayed normal M. avium-induced tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses. This finding was confirmed by determining the number of splenic CD4(+) T cells producing IFN-γ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-α production by M. avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes in M. avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control of M. avium infection is not related to the induction of Th1 responses.     

Local and remote tissue injury upon intestinal ischemia and reperfusion depends on the TLR/MyD88 signaling pathway

Innate immune responses against microorganisms may be mediated by Toll-like receptors (TLRs). Intestinal ischemia–reperfusion (i-I/R) leads to the translocation of bacteria and/or bacterial products such as endotoxin, which activate TLRs leading to acute intestinal and lung injury and inflammation observed upon gut trauma. Here, we investigated the role of TLR activation by using mice deficient for the common TLR adaptor protein myeloid differentiation factor 88 (MyD88) on local and remote inflammation following intestinal ischemia. Balb/c and MyD88^?/? mice were subjected to occlusion of the superior mesenteric artery (45 min) followed by intestinal reperfusion (4 h). Acute neutrophil recruitment into the intestinal wall and the lung was significantly diminished in MyD88^?/? after i-I/R, which was confirmed microscopically. Diminished neutrophil recruitment was accompanied with reduced concentration of TNF-α and IL-1β level. Furthermore, diminished microvascular leak and bacteremia were associated with enhanced survival of MyD88^?/? mice. However, neither TNF-α nor IL-1β neutralization prevented neutrophil recruitment into the lung but attenuated intestinal inflammation upon i-I/R. In conclusion, our data demonstrate that disruption of the TLR/MyD88 pathway in mice attenuates acute intestinal and lung injury, inflammation, and endothelial damage allowing enhanced survival.     

黄芪甲苷通过toll样受体4/核因子κB通路介导辐射所致肾损伤的防护作用

目的 探讨黄芪甲苷(AS-Ⅳ)是否通过toll样受体4(TLR4)/核因子κB(NF-KB)介导的信号通路对辐射诱导肾脏损伤起到保护作用.方法 将小鼠分为正常对照组、DMSO溶剂组、辐射组(IR)、IR+AS-Ⅳ20 mg/kg组和IR+AS-Ⅳ 40 mg/kg组.小鼠给予AS-Ⅳ腹腔注射1个月后,以8Gy的60Co...     

小檗碱和育亨宾对内毒素血症小鼠脾脏TLR4信号通路中相关基因表达的影响

目的: 观察小檗碱和α₂肾上腺素能受体拮抗剂育亨宾对内毒素血症小鼠脾脏Toll样受体4(TLR4)信号通路84种基因表达的影响,并初步探讨其作用机制。方法: 雄性BALB/c小鼠随机分为对照组、脂多糖(LPS)组、小檗碱+LPS组、小檗碱+育亨宾+LPS组、育亨宾+LPS组、小檗碱组、小檗碱+育亨宾组和育亨宾组。分别用蒸馏水、小檗碱(50 mg/kg)、小檗碱+育亨宾(50 mg/kg+2 mg/kg) 和育亨宾(2 mg/kg)灌胃,每天1次,连续3 d,第3 d灌胃1 h后,腹腔注射LPS(20 mg/kg)或生理盐水。腹腔注射1 h后,用RT² Profiler^TM PCR Array分析技术检测小鼠脾脏TLR4信号通路84种基因mRNA的表达;用Western blotting分析小鼠脾脏TLR4信号通路的抑制分子细胞因子信号抑制物(SOCS)1、SOCS3和白细胞介素-1受体相关激酶(IRAK)-M蛋白的表达。结果: LPS可上调小鼠脾脏TLR4信号转导通路中相关炎症因子的mRNA表达,包括CXCL10、TNF-α、IL-1α、IL-1β、IL-6、IFN-γ和IFN-β。小檗碱能显著下调下调髓样分化因子(MyD88)依赖信号通路下游TNF-α、IL-1α、IL-1β和IL-6 mRNA的表达,也能MyD88非依赖信号通路下游基因IFN-β和CXCL10 mRNA的表达(P<0.05)。育亨宾能显著下调内毒素血症小鼠脾脏IL-1α、IL-1β 和IFN-β mRNA的表达(P<0.05),但对TNF-α、IL-6和CXCL10 mRNA表达的下调作用与LPS组相比没有显著差异(P>0.05)。小檗碱与育亨宾合剂能显著下调内毒素血症小鼠脾脏IFN-β和CXCL10 mRNA的表达,但不能显著下调内毒素血症小鼠脾脏IL-1α、IL-1β、TNF-α 和IL-6 mRNA的表达。LPS攻击后1 h,小檗碱和(或)育亨宾均不能增强内毒素血症小鼠脾脏SOCS1、SOCS3和IRAK-M蛋白的表达。结论: 小檗碱和育亨宾均能抑制LPS诱导的MyD88依赖和非依赖信号通路下游部分基因的表达,这种抑制作用的机制与SOCS1、SOCS3和IRAK-M蛋白无关。     

绿茶多酚通过抑制TLR4通路减轻蛛网膜下腔出血大鼠早期脑损伤

目的 探讨绿茶多酚通过抑制TLR4通路对蛛网膜下腔出血大鼠早期脑损伤的影响.方法 建立大鼠蛛网膜下腔出血模型,随机分为模型组、绿茶多酚组、TAK-242(TLR4抑制剂)组、绿茶多酚+TAK-242组,每组12只;另取12只大鼠设为假手术组.药物处理后,对所有大鼠进行神经功能缺损评分,检测各组大鼠脑组织含水量,采用Ev...     

Epithelial-specific blockade of MyD88-dependent pathway causes spontaneous small intestinal inflammation

Accumulating evidence suggests a role for Toll-like receptor (TLR) signaling at the intestinal epithelial cells (IECs) level for intestinal protection against exogenous injury or pathogenic infection. We hypothesized that MyD88 dependent TLR signaling at intestinal epithelium is critical for mucosal immune homeostasis. In the current study, a transgenic mouse model was generated in which a dominant-negative mutant of MyD88 (dnMyD88) was driven by an intestinal epithelial-specific murine villin promoter. Aged transgenic mice spontaneously developed chronic small intestinal inflammation, as revealed by increased CD4+ and CD8+ lymphocytes, neutrophil and macrophage infiltration, increased production of cytokines as TNF-α, IFN-γ, IL-1β, and IL-17, crypt abscesses, lymphedema, and Goblet cell depletion. The chronic inflammation was not due to increased epithelial apoptosis or permeability, but to a decreased Paneth cell-derived α-defensins (cryptdins) and RegIII-γ and increased commensal bacteria translocation. Thus, epithelial MyD88-dependent pathway plays an essential role in limiting mucosal microflora penetration and preventing mucosal immunoregulation disturbance in vivo.     

舒利迭联合孟鲁司特治疗咳嗽变异性哮喘患者气道炎症的影响分析

目的 探讨舒利迭联合孟鲁司特治疗咳嗽变异性哮喘患者气道炎症的影响.方法 选择2015年3月至2016年3月我院诊治的咳嗽变异性哮喘患者70例作为研究对象.按随机数表法分为观察组和对照组各35例.对照组采用舒利迭进行治疗,观察组在对照组的基础上联合孟鲁司特进行治疗.比较两组患者的症状改善用时情况、肺通气功能、促炎症细胞因子水平、嗜酸性粒细胞(Eosinophil,Eos)及呼出气一氧化氮(Fractional exhaled nitric oxide,FeNO)水平.结果 治疗后,观察组症状缓解和消失用时均短于对照组[(6.05±1.44)d比(7.21±1.52)d,(7.63±1.75)d比(8.74±1.58)d](P<0.05);观察组患者肺通气功能中第1秒用力呼气容积(FEV 1)、第1秒用力呼气容积占预计值百分比(FEV 1/pred)、第1秒用力呼气容积占用力肺活量比值(FEV 1/FVC)及呼气峰流速占预计值百分比(PEF/pred)均高于对照组(P<0.05);观察组的白细胞介素(interleukin,IL)-12高于对照组[(84.26±10.97)ng/L比(68.13±9.82)ng/L](P<0.05),肿瘤坏死因子 α(tumour necrosis factor-α,TNF-α)及IL-6均低于对照组[(0.65±0.13)ng/L比(0.94±0.16)ng/L,(14.11±3.78)ng/L比(20.43±4.14)ng/L](P<0.05);观察组患者的Eos及FeNO均低于对照组[(2.61±1.75)%比(5.34±2.03)%,(45.68±11.43)ppb比(78.46±18.42)ppb](P<0.05).结论 舒利迭联合孟鲁司特治疗咳嗽变异性哮喘能有效改善患者肺通气功能,缩短治疗时间,缓解患者气道炎症并改善患者的炎症反应状态,效果显著,值得推广.