TLR4信号通路基因SNPs与脓毒症易感性的相关性研究
|
摘要
背景和目的：
脓毒症是临床危重患者的主要死亡原因之一,复杂发病机制及高死亡率使其成为世界性重症医学研究的难点和热点。越来越多的研究发现脓毒症的产生和转归具有明显的遗传背景,免疫反应通路内基因的突变,尤其是单核苷酸多态性(single nucleotide polymorphism, SNPs),可影响机体免疫系统对病原体的反应程度。固有免疫受体Toll样受体4(Toll-like receptor4,TLR4)及其信号通路在脓毒症的发生和发展过程中发挥着重要的作用,既往有研究显示TLR4及其信号通路中重要分子基因SNPs与脓毒症易感性相关,其中研究最多的是TLR4Asp299Gly/Thr399Ile(rs4986790/rs4986791)和CD14C-159T(rs2569190)三个SNPs,但各项研究结果并不一致,多种因素导致这种差异性结果的产生,其中不同人种SNPs存在的差异以及多基因多位点的相互影响被认为是主要的原因。本研究拟进一步探讨这些SNPs与脓毒症易感性的相关性,同时继续寻找该通路中可能会影响脓毒症发生风险的其他SNPs,并分析这些SNPs在脓毒症发生过程中的相互作用。
方法：
在MEDLINE, EMBASE和Web of Science数据库内,对以往关于TLR4Asp299Gly和Thr399Ile多态性与脓毒症易感性相关性的文献进行全面检索,通过对多项研究结果进行Met a分析来探讨TLR4Asp299Gly和Thr399Ile多态性与人类脓毒症易感性的相关性,并计算比值比(odds ratios, ORs)和95%可信区间(confidence intervals, CIs)。课题第二部分继续利用生物信息学方法筛选TLR4及其信号通路中与TLR4相互作用的分化抗原簇14(cluster of differentiation14, CD14)、髓样分化蛋白2(myeloid differentiation2, MD2)和Toll/白介素-1受体相关蛋白(Toll/interleukin-1receptor-associated protein/MyD88-adaptor-like, TIRAP/Mal)基因的SNPs进行研究,入选的SNPs包括以往有报道显示与免疫炎症性疾病相关的SNPs或基因的标签SNPs,运用基质辅助激光解吸附电离飞行时间质谱(matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, MALDI-TOF MS)技术检测SNPs基因型,通过病例对照研究的方法探讨这些SNPs与中国汉族人脓毒症易感性的相关性,并运用多因素维度减少(Multifactor Dimensionality Reduction, MDR)软件进行SNP-SNP相互作用的分析。最后,通过体外试验观察相关SNP不同基因型个体全血白细胞对脂多糖(lipopolysaccharide, LPS)刺激的反应性的差异,以验证相关SNP的生物学功能。
结果：
17项包含2212例脓毒症患者和3880例对照者的研究入选关于TLR4Asp299Gly多态性与脓毒症易感性相关性的Meta分析,其中10项包含711例脓毒症患者和1376例对照者的研究入选关于TLR4Thr399Ile多态性与脓毒症易感性相关性的Meta分析,研究对象主要为高加索人。TLR4Asp299Gly多态性与脓毒症易感性相关性的总Meta分析OR值为1.22(95%CI：0.90-1.65,P==0.21),TLR4Thr399Ile多态性与脓毒症易感性相关性的总Meta分析OR值为1.16(95%CI：0.70-1.91,P==0.57)。对革兰氏阴性菌和混合微生物感染所致脓毒症进行的亚组Meta分析和敏感性检验也都显示TLR4Asp299Gly和Thr399Ile多态性与高加索人的脓毒症易感性无显著相关性。课题第二部分筛选出4个基因的7个SNPs进行检测,包括TLR4rs10759932、TLR4rs11536889、MD2rs10808798、CD14rs2569190和三个TIRAP/Mal基因标签SNPs (rs8177352、rs595209和lrs8177375),病例对照研究共纳入336例脓毒症患者和359例对照患者,分为手术后组(99/105)和非手术后组(237/254)分别进行比较分析,两组统计结果均显示TIRAP/Mal rs595209多态性AC/CC基因型在脓毒症患者中的分布显著低于对照组患者(P<0.05),校正性别、年龄、基础疾病和手术方式等混杂因素后,TIRAP/Malrs595209多态性仍与中国汉族人群脓毒症易感性显著相关,两组OR值分别为0.287和0.508(95%CI,0.089-0.922,P=0.036；95%CI,0.282-0.918,P=0.025)。MDR分析结果显示,在影响脓毒症发生的过程中,不具有独立作用的MD2rs10808798、 TLR4rs10759932、TLR4rs11536889和CD14rs2569190多态性与脓毒症相关SNPTIRAP/Malrs595209具有协同作用,其中,MD2rs10808798和TLR4rs10759932这两个SNPs之间的相互作用关系最强。LPS刺激下,TIRAP/Mal rs595209多态性AC/CC基因型外周血TNF-a和IL-10生成水平显著低于AA基因型外周血,TIRAP/Malrs595209位点A>C的碱基变异能显著减弱全血白细胞对LPS的反应。
结论：
TLR4Asp299Gly和Thr399Ile多态性与高加索人革兰氏阴性菌脓毒症和全因脓毒症的发生风险无显著相关性。TIRAP/Malrs595209多态性与中国汉族人脓毒症的易感性显著相关,携带rs595209多态性AC或CC基因型的个体较携带AA基因型的个体发生脓毒症的风险低。在脓毒症发生过程中相互作用的TIRAP/Mal、MD2、 TLR4和CD14,其基因SNPs(TIRAP/Malrs595209、MD2rs10808798、TLR4rs10759932、 TLR4rs11536889和CD14rs2569190)也在影响脓毒症发生的过程中产生协同作用。TIRAP/Malrs595209是一个功能性基因变异位点,可能可以作为风险预测指标来评估患者的脓毒症发生风险。
Backgrounds and aims:
Sepsis is a main cause of death of critical ill patients. With complex pathogenesis and high mortality, sepsis has become a problem worldwide. More and more studies show that genetic factors influence the development and outcome of sepsis. Genetic variants, especially the single-nucleotide polymorphisms (SNPs), in the immune response pathway genes can affect the host immune responses to pathogens. TLR4, an innate immune receptor, and its single pathway play an important role in the development of sepsis. Previous studies have indicated that SNPs in TLR4and its single pathway genes are associated with the susceptibility to sepsis. TLR4Asp299Gly/Thr399Ile and CD14C-159T polymorphisms were mostly reported. However, the results are inconsistent and inconclusive. A variety of factors lead to these inconsistent results. The differences of SNPs existing in diferect populations and the interactions of SNPs in multiple genes have been considered to be the main reasons. Therefore, our purposes in this work were to find more sepsis-related SNPs in this pathway and simultaneously evaluate interactions between these SNPs within genes confined to a single pathway, while we further study the relations between these SNPs and the susceptibility to sepsis.
Methods:
Electronic searches of MEDLINE, EMBASE and Web of Science databases were performed. Original observational studies dealing with the association between polymorphisms Asp299Gly and/or Thr399Ile and sepsis risk were selected. The associations of these two common polymorphisms with sepsis susceptibility were estimated by performing a meta-analysis of previous data. Odds ratios (ORs) and95%confidence intervals (CIs) were calculated with random-effects model or fixed-effects model based on the heterogeneity analysis.The potential SNPs in TLR4、CD14、MD2and TIRAP/Mal genes were selected through bioinformatics analysis, including SNPs previously reported to be associated with immune and inflammatory diseases and tag SNPs. Genotypes of seven SNPs in four candidate genes were detected with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). We conducted a case control study to investigate the associations of theses SNPs and the susceptibility to sepsis in Chinese Han population, and studied the SNP-SNP interactions using Multifactor Dimensionality Reduction (MDR). Finally, ex vivo LPS stimulation of human whole blood was performed to detect the associations of different genotypes of the related SNP and cytokine productions for functional evaluation of the related SNP.
Results:
Seventeen studies including2212cases and3880controls were included in the Meta-analysis for the association of Asp299Gly polymorphism with sepsis risk, and ten studies including711cases and1376controls were included in the Meta-analysis for the association of Thr399Ile polymorphism with sepsis risk. Most subjects were Caucasian populations. The odds ratio for the association of Asp299Gly polymorphism with sepsis risk was1.22(95%CI:0.90-1.65, P=0.21), and the association of Thr399Ile polymorphism was1.16(95%CI:0.70-1.91, P=0.57). Subgroup analysis and sensitivity analysis did not change the results. Seven SNPs in four genes were selected and genotyped,including TLR4rs10759932TLR4rs11536889、MD2rs10808798、CD14rs2569190and3tag SNPs in TIRAP/Mal gene (rs8177352、rs595209and rs8177375). Three hundred and thirty six patients with sepsis and three hundred and fifty nine control patients were enrolled.All subjects were divided into operation group and non-operation group. The TIRAP/Mal rs595209polymorphism AC/CC genotypes were significantly lower in sepsis patients than in control patients in two groups (P<0.05).After adjustment for age, gender, baseline conditions and surgery types, TIRAP/Mal rs595209polymorphism was significantly associated with the lower risk of sepsis in Chinese Han populations (OR=0.287,95%CI,0.089-0.922, P=0.036; OR=0.508,95%CI,0.282-0.918, P=0.025, respectively). Moreover, Multifactor Dimensionality Reduction analysis showed significant interactions between MD2rs10808798, TLR4rs10759932, TLR4rs11536889. CD14rs2569190and TIRAP/Malrs595209polymorphisms in the development of sepsis. The strongest interaction existed between MD2rs10808798and TLR4rs10759932polymorphisms. Under LPS-stimulation, the concentrations of TNF-a and IL-10in supernatants of the whole blood carrying TIRAP/Malrs595209AC/CC genotypes were significantly lower in those of AA genotype. Genetic variation (A> C) in TIRAP/Malrs595209locus significantly reduced whole blood leukocyte response to LPS.
Conclusions:
The two common TLR4SNPs (Asp299Gly and Thr399Ile) have no strong association with the risk of gram-negative bacteria sepsis and all-cause sepsis in Caucasian populations. TIRAP/Malrs595209polymorphism was significantly associated with the lower risk of developing sepsis in Chinese Han populations. Carriage of AC/CC genotype of TIRAP/Malrs595209polymorphism imparted a decreased sepsis risk. A combination of MD2rs10808798, TLR4rs10759932, TLR4rs11536889, CD14rs2569190and TIRAP/Malrs595209had a synergistic effect in the development of sepsis. TIRAP/Malrs595209polymorphism is a functional variation and might be used as a risk estimate for sepsis in patients.
脓毒症是临床危重患者的主要死亡原因之一,复杂发病机制及高死亡率使其成为世界性重症医学研究的难点和热点。越来越多的研究发现脓毒症的产生和转归具有明显的遗传背景,免疫反应通路内基因的突变,尤其是单核苷酸多态性(single nucleotide polymorphism, SNPs),可影响机体免疫系统对病原体的反应程度。固有免疫受体Toll样受体4(Toll-like receptor4,TLR4)及其信号通路在脓毒症的发生和发展过程中发挥着重要的作用,既往有研究显示TLR4及其信号通路中重要分子基因SNPs与脓毒症易感性相关,其中研究最多的是TLR4Asp299Gly/Thr399Ile(rs4986790/rs4986791)和CD14C-159T(rs2569190)三个SNPs,但各项研究结果并不一致,多种因素导致这种差异性结果的产生,其中不同人种SNPs存在的差异以及多基因多位点的相互影响被认为是主要的原因。本研究拟进一步探讨这些SNPs与脓毒症易感性的相关性,同时继续寻找该通路中可能会影响脓毒症发生风险的其他SNPs,并分析这些SNPs在脓毒症发生过程中的相互作用。
方法：
在MEDLINE, EMBASE和Web of Science数据库内,对以往关于TLR4Asp299Gly和Thr399Ile多态性与脓毒症易感性相关性的文献进行全面检索,通过对多项研究结果进行Met a分析来探讨TLR4Asp299Gly和Thr399Ile多态性与人类脓毒症易感性的相关性,并计算比值比(odds ratios, ORs)和95%可信区间(confidence intervals, CIs)。课题第二部分继续利用生物信息学方法筛选TLR4及其信号通路中与TLR4相互作用的分化抗原簇14(cluster of differentiation14, CD14)、髓样分化蛋白2(myeloid differentiation2, MD2)和Toll/白介素-1受体相关蛋白(Toll/interleukin-1receptor-associated protein/MyD88-adaptor-like, TIRAP/Mal)基因的SNPs进行研究,入选的SNPs包括以往有报道显示与免疫炎症性疾病相关的SNPs或基因的标签SNPs,运用基质辅助激光解吸附电离飞行时间质谱(matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, MALDI-TOF MS)技术检测SNPs基因型,通过病例对照研究的方法探讨这些SNPs与中国汉族人脓毒症易感性的相关性,并运用多因素维度减少(Multifactor Dimensionality Reduction, MDR)软件进行SNP-SNP相互作用的分析。最后,通过体外试验观察相关SNP不同基因型个体全血白细胞对脂多糖(lipopolysaccharide, LPS)刺激的反应性的差异,以验证相关SNP的生物学功能。
结果：
17项包含2212例脓毒症患者和3880例对照者的研究入选关于TLR4Asp299Gly多态性与脓毒症易感性相关性的Meta分析,其中10项包含711例脓毒症患者和1376例对照者的研究入选关于TLR4Thr399Ile多态性与脓毒症易感性相关性的Meta分析,研究对象主要为高加索人。TLR4Asp299Gly多态性与脓毒症易感性相关性的总Meta分析OR值为1.22(95%CI：0.90-1.65,P==0.21),TLR4Thr399Ile多态性与脓毒症易感性相关性的总Meta分析OR值为1.16(95%CI：0.70-1.91,P==0.57)。对革兰氏阴性菌和混合微生物感染所致脓毒症进行的亚组Meta分析和敏感性检验也都显示TLR4Asp299Gly和Thr399Ile多态性与高加索人的脓毒症易感性无显著相关性。课题第二部分筛选出4个基因的7个SNPs进行检测,包括TLR4rs10759932、TLR4rs11536889、MD2rs10808798、CD14rs2569190和三个TIRAP/Mal基因标签SNPs (rs8177352、rs595209和lrs8177375),病例对照研究共纳入336例脓毒症患者和359例对照患者,分为手术后组(99/105)和非手术后组(237/254)分别进行比较分析,两组统计结果均显示TIRAP/Mal rs595209多态性AC/CC基因型在脓毒症患者中的分布显著低于对照组患者(P<0.05),校正性别、年龄、基础疾病和手术方式等混杂因素后,TIRAP/Malrs595209多态性仍与中国汉族人群脓毒症易感性显著相关,两组OR值分别为0.287和0.508(95%CI,0.089-0.922,P=0.036；95%CI,0.282-0.918,P=0.025)。MDR分析结果显示,在影响脓毒症发生的过程中,不具有独立作用的MD2rs10808798、 TLR4rs10759932、TLR4rs11536889和CD14rs2569190多态性与脓毒症相关SNPTIRAP/Malrs595209具有协同作用,其中,MD2rs10808798和TLR4rs10759932这两个SNPs之间的相互作用关系最强。LPS刺激下,TIRAP/Mal rs595209多态性AC/CC基因型外周血TNF-a和IL-10生成水平显著低于AA基因型外周血,TIRAP/Malrs595209位点A>C的碱基变异能显著减弱全血白细胞对LPS的反应。
结论：
TLR4Asp299Gly和Thr399Ile多态性与高加索人革兰氏阴性菌脓毒症和全因脓毒症的发生风险无显著相关性。TIRAP/Malrs595209多态性与中国汉族人脓毒症的易感性显著相关,携带rs595209多态性AC或CC基因型的个体较携带AA基因型的个体发生脓毒症的风险低。在脓毒症发生过程中相互作用的TIRAP/Mal、MD2、 TLR4和CD14,其基因SNPs(TIRAP/Malrs595209、MD2rs10808798、TLR4rs10759932、 TLR4rs11536889和CD14rs2569190)也在影响脓毒症发生的过程中产生协同作用。TIRAP/Malrs595209是一个功能性基因变异位点,可能可以作为风险预测指标来评估患者的脓毒症发生风险。
Backgrounds and aims:
Sepsis is a main cause of death of critical ill patients. With complex pathogenesis and high mortality, sepsis has become a problem worldwide. More and more studies show that genetic factors influence the development and outcome of sepsis. Genetic variants, especially the single-nucleotide polymorphisms (SNPs), in the immune response pathway genes can affect the host immune responses to pathogens. TLR4, an innate immune receptor, and its single pathway play an important role in the development of sepsis. Previous studies have indicated that SNPs in TLR4and its single pathway genes are associated with the susceptibility to sepsis. TLR4Asp299Gly/Thr399Ile and CD14C-159T polymorphisms were mostly reported. However, the results are inconsistent and inconclusive. A variety of factors lead to these inconsistent results. The differences of SNPs existing in diferect populations and the interactions of SNPs in multiple genes have been considered to be the main reasons. Therefore, our purposes in this work were to find more sepsis-related SNPs in this pathway and simultaneously evaluate interactions between these SNPs within genes confined to a single pathway, while we further study the relations between these SNPs and the susceptibility to sepsis.
Methods:
Electronic searches of MEDLINE, EMBASE and Web of Science databases were performed. Original observational studies dealing with the association between polymorphisms Asp299Gly and/or Thr399Ile and sepsis risk were selected. The associations of these two common polymorphisms with sepsis susceptibility were estimated by performing a meta-analysis of previous data. Odds ratios (ORs) and95%confidence intervals (CIs) were calculated with random-effects model or fixed-effects model based on the heterogeneity analysis.The potential SNPs in TLR4、CD14、MD2and TIRAP/Mal genes were selected through bioinformatics analysis, including SNPs previously reported to be associated with immune and inflammatory diseases and tag SNPs. Genotypes of seven SNPs in four candidate genes were detected with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). We conducted a case control study to investigate the associations of theses SNPs and the susceptibility to sepsis in Chinese Han population, and studied the SNP-SNP interactions using Multifactor Dimensionality Reduction (MDR). Finally, ex vivo LPS stimulation of human whole blood was performed to detect the associations of different genotypes of the related SNP and cytokine productions for functional evaluation of the related SNP.
Results:
Seventeen studies including2212cases and3880controls were included in the Meta-analysis for the association of Asp299Gly polymorphism with sepsis risk, and ten studies including711cases and1376controls were included in the Meta-analysis for the association of Thr399Ile polymorphism with sepsis risk. Most subjects were Caucasian populations. The odds ratio for the association of Asp299Gly polymorphism with sepsis risk was1.22(95%CI:0.90-1.65, P=0.21), and the association of Thr399Ile polymorphism was1.16(95%CI:0.70-1.91, P=0.57). Subgroup analysis and sensitivity analysis did not change the results. Seven SNPs in four genes were selected and genotyped,including TLR4rs10759932TLR4rs11536889、MD2rs10808798、CD14rs2569190and3tag SNPs in TIRAP/Mal gene (rs8177352、rs595209and rs8177375). Three hundred and thirty six patients with sepsis and three hundred and fifty nine control patients were enrolled.All subjects were divided into operation group and non-operation group. The TIRAP/Mal rs595209polymorphism AC/CC genotypes were significantly lower in sepsis patients than in control patients in two groups (P<0.05).After adjustment for age, gender, baseline conditions and surgery types, TIRAP/Mal rs595209polymorphism was significantly associated with the lower risk of sepsis in Chinese Han populations (OR=0.287,95%CI,0.089-0.922, P=0.036; OR=0.508,95%CI,0.282-0.918, P=0.025, respectively). Moreover, Multifactor Dimensionality Reduction analysis showed significant interactions between MD2rs10808798, TLR4rs10759932, TLR4rs11536889. CD14rs2569190and TIRAP/Malrs595209polymorphisms in the development of sepsis. The strongest interaction existed between MD2rs10808798and TLR4rs10759932polymorphisms. Under LPS-stimulation, the concentrations of TNF-a and IL-10in supernatants of the whole blood carrying TIRAP/Malrs595209AC/CC genotypes were significantly lower in those of AA genotype. Genetic variation (A> C) in TIRAP/Malrs595209locus significantly reduced whole blood leukocyte response to LPS.
Conclusions:
The two common TLR4SNPs (Asp299Gly and Thr399Ile) have no strong association with the risk of gram-negative bacteria sepsis and all-cause sepsis in Caucasian populations. TIRAP/Malrs595209polymorphism was significantly associated with the lower risk of developing sepsis in Chinese Han populations. Carriage of AC/CC genotype of TIRAP/Malrs595209polymorphism imparted a decreased sepsis risk. A combination of MD2rs10808798, TLR4rs10759932, TLR4rs11536889, CD14rs2569190and TIRAP/Malrs595209had a synergistic effect in the development of sepsis. TIRAP/Malrs595209polymorphism is a functional variation and might be used as a risk estimate for sepsis in patients.
引文
[1]Cheng B., Xie G., Yao S., et al., Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Crit Care Med,2007.35(11):2538-2546.
[2]Nee P.A., Critical care in the emergency department:severe sepsis and septic shock. Emerg Med J,2006.23(9):713-717.
[3]Angus D.C., Linde-Zwirble W.T., Lidicker J., et al., Epidemiology of severe sepsis in the United States:analysis of incidence, outcome, and associated costs of care. Crit Care Med,2001. 29(7):1303-1310.
[4]Abraham E., Laterre P.F., Garbino J., et al., Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock:a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med,2001. 29(3):503-510.
[5]Lopez A., Lorente J.A., Steingrub J., et al., Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88:effect on survival in patients with septic shock. Crit Care Med,2004.32(1):21-30.
[6]Opal S., Laterre P.F., Abraham E., et al., Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis:results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med,2004.32(2):332-341.
[7]Cinel I. and Opal S.M., Molecular biology of inflammation and sepsis:a primer. Crit Care Med, 2009.37(l):291-304.
[8]Teuffel O., Ethier M.C., Beyene J., et al., Association between tumor necrosis factor-alpha promoter -308 A/G polymorphism and susceptibility to sepsis and sepsis mortality:a systematic review and meta-analysis. Crit Care Med,2010.38(1):276-282.
[9]Majetschak M., Obertacke U., Schade F.U., et al., Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma patients. Clin Diagn Lab Immunol, 2002.9(6):1205-1211.
[10]Stanilova S.A., Functional relevance of IL-10 promoter polymorphisms for sepsis development. Crit Care,2010.14(1):119.
[11]Barber R.C., Aragaki C.C., Chang L.Y., et al., CD14-159 C allele is associated with increased risk of mortality after burn injury. Shock,2007.27(3):232-237.
[12]Medzhitov R., Preston-Hurlburt P. and Janeway C.A., Jr., A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature,1997. 388(6640):394-397.
[13]Barreiro L.B., Ben-Ali M., Quach H., et al., Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense. PLoS Genet,2009.5(7):e1000562.
[14]Akira S. and Takeda K., Toll-like receptor signalling. Nat Rev Immunol,2004.4(7):499-511.
[15]Hoshino K., Takeuchi O., Kawai T., et al., Cutting edge:Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide:evidence for TLR4 as the Lps gene product.J Immunol,1999.162(7):3749-3752.
[16]Poltorak A., Smirnova I., He X., et al., Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol Dis,1998.24(3):340-355.
[17]Bochud P.Y., Chien J.W., Marr K.A., et al., Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med,2008.359(17):1766-1777.
[18]Kupcinskas J., Wex T., Bornschein J., et al., Lack of association between gene polymorphisms of Angiotensin converting enzyme, Nod-like receptor 1, Toll-like receptor 4, FAS/FASL and the presence of Helicobacter pylori-induced premalignant gastric lesions and gastric cancer in Caucasians, BMC Med Genet,2011.12:112.
[19]Zhou H., Andonegui G., Wong C.H., et al.. Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. J Immunol,2009. 183(8):5244-5250.
[20]Hu G., Malik A.B. and Minshall R.D., Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation. Crit Care Med,2010.38(1):194-201.
[21]Rumbaut R.E., Bellera R.V., Randhawa J.K., et al., Endotoxin enhances microvascular thrombosis in mouse cremaster venules via a TLR4-dependent, neutrophil-independent mechanism. Am J Physiol Heart Circ Physiol,2006.290(4):H1671-1679.
[22]Zhang G., Han J., Welch E.J., et al., Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol,2009.182(12):7997-8004.
[23]Ferwerda B., McCall M.B., Alonso S., et al., TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans. Proc Natl Acad Sci U S A,2007. 104(42):16645-16650.
[24]Arbour N.C., Lorenz E., Schutte B.C., et al., TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet,2000.25(2):187-191.
[25]Lorenz E., Mira J.P., Frees K.L., et al.. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med,2002.162(9):1028-1032.
[26]Ahrens P., Kattner E., Kohler B., et al., Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants. Pediatr Res,2004. 55(4):652-656.
[27]Read R.C., Pullin J., Gregory S., et al., A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis,2001. 184(5):640-642.
[28]Agnese D.M., Calvano J.E., Hahm S.J., et al., Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis,2002.186(10):1522-1525.
[29]Smirnova I., Mann N., Dols A., et al., Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci U S A,2003. 100(10):6075-6080.
[30]Feterowski C., Emmanuilidis K., Miethke T., et al., Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis. Immunology,2003. 109(3):426-431.
[31]Van der Graaf C.A., Netea M.G., Morre S.A., et al., Toll-like receptor 4 Asp299Gly/Thr399lle polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw,2006. 17(1):29-34.
[32]Everett B., Cameron B., Li H., et al., Polymorphisms in Toll-like receptors-2 and -4 are not associated with disease manifestations in acute Q fever. Genes Immun,2007.8(8):699-702.
[33]Yuan F.F., Marks K., Wong M., et al., Clinical relevance of TLR2, TLR4, CD14 and FcgammaRIIA gene polymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol,2008. 86(3):268-270.
[34]Henckaerts L., Nielsen K.R., Steffensen R., et al., Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med,2009. 37(1):192-201, e191-193.
[35]Mensah N.Y., Peterlongo P., Steinherz P., et al., Toll-like receptor 4 polymorphisms and risk of gram-negative bacteremia after allogeneic stem cell transplantation. A prospective pilot study. Biol Blood Marrow Transplant,2009.15(9):1130-1133.
[36]Horcajada J.P., Lozano F., Munoz A., et al., Polymorphic receptors of the innate immune system (MBL/MASP-2 and TLR2/4) and susceptibility to pneumococcal bacteremia in HIV-infected patients:a case-control study. Curr HIV Res,2009.7(2):218-223.
[37]Ozgur T.T., Yel L., Yigit S., et al.. Lack of association between TLR4 polymorphism and severe gram-negative bacterial infection in neonates. Turkish Journal of Medical Sciences,2009. 39(3):423-427.
[38]Kumpf O., Giamarellos-Bourboulis E.J., Koch A., et al., Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release:an observational study in three cohorts. Crit Care,2010.14(3):R103.
[39]Guarner-Argente C., Sanchez E., Vidal S., et al., Toll-like receptor 4 D299G polymorphism and the incidence of infections in cirrhotic patients. Aliment Pharmacol Ther,2010. 31(11):1192-1199.
[40]Carregaro F., Carta A., Cordeiro J.A., et al., Polymorphisms IL10-819 and TLR-2 are potentially associated with sepsis in Brazilian patients. Mem Inst Oswaldo Cruz,2010.105(5):649-656.
[41]Ahmad-Nejad P., Denz C., Zimmer W., et al., The Presence of Functionally Relevant Toll-Like Receptor Polymorphisms Does Not Significantly Correlate with Development or Outcome of Sepsis. Genetic Testing and Molecular Biomarkers,2011.15(9):645-651.
[42]Kajikawa O., Frevert C.W., Lin S.M., et al., Gene expression of Toll-like receptor-2, Toll-like receptor-4, and MD2 is differentially regulated in rabbits with Escherichia coli pneumonia. Gene,2005.344:193-202.
[43]van der Graaf C., Kullberg B.J., Joosten L., et al., Functional consequences of the Asp299Gly Toll-like receptor-4 polymorphism. Cytokine,2005.30(5):264-268.
[44]Schippers E.F., van't Veer C., van Voorden S., et al., IL-10 and toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. Cytokine,2005. 29(5):215-228.
[45]Calvano J.E., Bowers D.J., Coyle S.M., et al., Response to systemic endotoxemia among humans bearing polymorphisms of the Toll-like receptor 4 (hTLR4). Clin Immunol,2006. 121(2):186-190.
[46]Fitzgerald K.A., Palsson-McDermott E.M., Bowie A.G., et al., Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature,2001.413(6851):78-83.
[47]Villar J., Maca-Meyer N., Perez-Mendez L., et al.,Bench-to-bedside review:understanding genetic predisposition to sepsis. Crit Care,2004.8(3):180-189.
[48]Levy M.M., Fink M.P., Marshall J.C., et al.,2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med,2003.31(4):1250-1256.
[49]Ritchie M.D., Hahn LW. and Moore J.H., Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol,2003.24(2):150-157.
[50]Moore J.H., Gilbert J.C., Tsai C.T., et al., A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol,2006.241(2):252-261.
[51]Kimman T.G., Banus S., Reijmerink N., et al., Association of interacting genes in the toll-like receptor signaling pathway and the antibody response to pertussis vaccination. PLoS One, 2008.3(11):e3665.
[52]Dhiman N., Ovsyannikova I.G., Vierkant R.A., et al., Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine:preliminary results. Vaccine,2008.26(14):1731-1736.
[53]Song Z., Yin J., Yao C., et al., Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population. Crit Care,2011.15(1):R12.
[54]Abu-Maziad A., Schaa K., Bell E.F., et al., Role of polymorphic variants as genetic modulators of infection in neonatal sepsis. Pediatr Res,2010.68(4)323-329.
[55]Barber R.C., Chang L.Y., Arnoldo B.D., et al., Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res,2006.4(4):250-255.
[56]Vogel S.N., Fitzgerald K.A. and Fenton M.J., TLRs:differential adapter utilization by toll-like receptors mediates TLR-specific patterns of gene expression. Mol Interv,2003.3(8):466-477.
[57]Hawn T.R., Dunstan S.J., Thwaites G.E., et al., A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. J Infect Dis,2006.194(8):1127-1134.
[58]Khor C.C., Chapman S.J., Vannberg F.O., et al., A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet,2007.39(4):523-528.
[59]Scott L.J., Mohlke K.L, Bonnycastle L.L., et al., A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science,2007. 316(5829):1341-1345.
[60]Nagai Y, Akashi S., Nagafuku M., et al., Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol,2002.3(7):667-672.
[61]Schromm A.B., Lien E., Henneke P., et al., Molecular genetic analysis of an endotoxin nonresponder mutant cell line:a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. J Exp Med,2001.194(1):79-88.
[62]Smit L.A., Heederik D., Doekes G., et al., Endotoxin exposure, CD14 and wheeze among farmers:a gene-environment interaction. Occup Environ Med,2011.
[63]Nguyen T.H., Mai N.L., Le T.P., et al., Toll-like receptor 4 (TLR4) and typhoid fever in Vietnam. PLoS One,2009.4(3):e4800.
[64]Duan Z.X., Gu W., Zhang L.Y., et al., Clinical relevance of the TLR4 11367 polymorphism in patients with major trauma. Arch Surg,2009.144(12):1144-1148.
[65]Chen K., Wang Y.T., Gu W., et al., Functional significance of the Toll-like receptor 4 promoter gene polymorphisms in the Chinese Han population. Crit Care Med,2010.38(5):1292-1299.
[66]Hishida A., Matsuo K., Goto Y, et al., Toll-like receptor 4+3725 G/C polymorphism, Helicobacter pylori seropositivity, and the risk of gastric atrophy and gastric cancer in Japanese. Helicobacter,2009.14(1):47-53.
[67]Zhou L., Wei B., Xing C., et al., Polymorphism in 3'-untranslated region of toll-like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantation. Transpl Infect Dis,2011.13(3):250-258.
[68]Duan Z.X., Zhu P.F., Dong H., et al., Functional significance of the TLR4/11367 polymorphism identified in Chinese Han population. Shock,2007.28(2):160-164.
[69]Tanguay R.L.and Gallie D.R., Translational efficiency is regulated by the length of the 3' untranslated region. Mol Cell Biol,1996.16(1):146-156.
[70]Penders J., Thijs C., Mommers M., et al., Host-microbial interactions in childhood atopy: toll-like receptor 4 (TLR4), CD14, and fecal Escherichia coli. J Allergy Clin Immunol,2010. 125(1):231-236 e231-235.
[71]Ferrero E., Jiao D., Tsuberi B.Z., et al., Transgenic mice expressing human CD14 are hypersensitive to lipopolysaccharide. Proc Natl Acad Sci U S A,1993.90(6):2380-2384.
[72]Carrillo E.H., Gordon L., Goode E., et al., Early elevation of soluble CD14 may help identify trauma patients at high risk for infection. J Trauma,2001.50(5):810-816.
[73]Burgmann H., Winkler S., Locker G.J., et al., Increased serum concentration of soluble CD14 is a prognostic marker in gram-positive sepsis. Clin Immunol Immunopathol,1996.80(3 Pt 1):307-310.
[74]Hubacek J.A., Stuber F., Frohlich D., et al., The common functional C(-159)T polymorphism within the promoter region of the lipopolysaccharide receptor CD14 is not associated with sepsis development or mortality. Genes Immun,2000. 1(6):405-407.
[75]Gu W., Dong H., Jiang D.P., et al., Functional significance of CD14 promoter polymorphisms and their clinical relevance in a Chinese Han population. Crit Care Med,2008. 36(8):2274-2280.
[76]Lin J., Yao Y.M., Yu Y., et al., Effects of CD14-159 C/T polymorphism on CD14 expression and the balance between proinflammatory and anti-inflammatory cytokines in whole blood culture. Shock,2007.28(2):148-153.
[77]de Aguiar B.B., Girardi I., Paskulin D.D., et al., CD14 expression in the first 24h of sepsis:effect of-260C>T CD14 SNP. Immunol Invest,2008.37(8):752-769.
[78]Kudsk K.A., Tolley E.A., DeWitt R.C., et al., Preoperative albumin and surgical site identify surgical risk for major postoperative complications. JPEN J Parenter Enteral Nutr,2003. 27(1):1-9.
[79]Azim K., McManus R., Brophy K., et al., Genetic polymorphisms and the risk of infection following esophagectomy. positive association with TNF-alpha gene -308 genotype. Ann Surg, 2007.246(1):122-128.
[80]Rodriguez F., Barrera L., De La Rosa G., et al., The epidemiology of sepsis in Colombia:a prospective multicenter cohort study in ten university hospitals. Crit Care Med,2011. 39(7):1675-1682.
[81]Jansky L., Reymanova P. and Kopecky J., Dynamics of cytokine production in human peripheral blood mononuclear cells stimulated by LPS or infected by Borrelia. Physiol Res, 2003.52(5):593-598.
[82]Lantos J., Foldi V., Roth E., et al., Burn trauma induces early HMGB1 release in patients:its correlation with cytokines. Shock,2010.33(6):562-567.
1. Medzhitov R, Preston-Hurlburt P, Janeway Jr CA. A human homologue of the Drosophila Toll proteins signals activation of adaptive immunity. Nature 1997; 388:394-7.
2. Sachidanandam, R., D. Weissman, S. C. Schmidt, J. M. et al. International SNP Map Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature,2001,409:928-33.
3. Janeway, C.A., Medzhltov, R. Innate immune recognition. Annu Rev Immunol, 2002,20:197-216.
4. Netea, M. G., C. A. Van Der Graaf, A. G. Vonk, et al. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J. Infect. Dis.2002,185:1483-9.
5. Poltorak, A., X. He, I. Smirnova, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice:mutations in Tlr4 gene. Science,1998,282:2085-8.
6. Hoshino K, Takeuchi 0, Kawai T, et al. Cutting edge:Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide:evidence for TLR4 as the Lps gene product. J Immunol,1999,162(7):3749-3752.
7. Zhou H, Andonegui G, Wong CH, et al. Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. J Immunol.2009,183(8):5244-50.
8. Hu G, Malik AB, Minshall RD. Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation. Crit Care Med.2010,38(1):194-201.
9. Zhang G, Han J, Welch EJ, Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol.2009,182(12):7997-8004.
10. Rumbaut RE, Bellera RV, Randhawa JK, Endotoxin enhances microvascular thrombosis in mouse cremaster venules via a TLR4-dependent, neutrophil-independent mechanism. Am J Physiol Heart Circ Physiol.2006, 290(4):H1671-9.
11. Rodriguez S, Chora A, Goumnerov B,Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. Blood.2009, 114(19):4064-76.
12. T. Roger, C. Froidevaux, D. Le Roy, et al., Protection from lethal Gram-negative bacterial sepsis by targeting Toll-like receptor 4. Proceedings of the National Academy of Sciences of the United States of America,2009,106(7): 2348-2352.
13. P. Groβ, K. Brandl, C. Dierkes, et al., Lipopolysaccharide-Trap-Fc, a multifunctional agent to battle gram-negative bacteria. Infection and Immunity,2009,77(7): 2925-2931.
14. Hong, Z. Jiang, W. Liangxi, et al., Chloroquine protects mice from challenge with CpG ODN and LPS by decreasing proinflammatory cytokine release. International Immunopharmacology,2004,4(2):223-234.
15. H. Methe, J.-O. Kim, S. Kofler, M. et al., Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Arteriosclerosis, Thrombosis, and Vascular Biology,2005,25(7):1439-1445.
16. Yu, D. Shao, J. Liu, J. et al. Effects of ketamine on levels of cytokines, NF-kB and TLRs in rat intestine during CLP-induced sepsis. International Immunopharmacology,2007,7(8):1076-1082.
17. L.-H. Guo, H. J. Schluesener, The innate immunity of the central nervous system in chronic pain:the role of Toll-like receptors. Cellular and Molecular Life Sciences, 2007,64(9):1128-1136.
18. Sackesen, C., C. Karaaslan, O. Keskin, N. et al. The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy,2005,60:1485-92.
19. Laine, M. L., S. A. Morre, L. S. Murillo, et al. CD14 and TLR4 gene polymorphisms in adult periodontitis. J. Dent. Res.2005,84:1042-1046.
20. Jeyaseelan, S., H. W. Chu, S. K. Young, et al. Distinct roles of pattern recognition receptors CD14 and Toll-like receptor 4 in acute lung injury. Infect. Immun.2005, 73:1754-63.
21. Chen, Y. C., E. Giovannucci, R. Lazarus, et al. Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res.2005, 65:11771-11778.
22. Kiechl, S., E. Lorenz, M. Reindl, C. J., et al. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med.2002,347:185-192.
23. Heesen, M., M. Wessiepe, D. Kunz, K. et al. Rapid and reliable genotyping for the Toll-like receptor 4 A896G polymorphism using fluorescence-labeled hybridization probes in a real-time polymerase chain reaction assay. Clin. Chim. Acta,2003,333:47-49.
24. Hawn TR, Scholes D, Li SS, et al. Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women.PLoS One.2009 Jun 22; 4(6):e5990.
25. Dahmer, M. K., A. Randolph, S. Vitali, et al. Genetic polymorphisms in sepsis. Pediatr. Crit. Care Me.2005,6(3 Suppl):S61-73.
26. Guo, Q. S., B. Xia, Y. Jiang, et al. Polymorphisms of CD14 gene and TLR4 gene are not associated with ulcerative colitis in Chinese patients. Postgrad. Med. J.2005, 81:526-529.
27. Lorenz, E., K. L. Frees, D. A. Schwartz. Determination of the TLR4 genotype using allele-specific PCR. Biotechniques,2001,31:22-24.
28. Saturnino SF, Andrade MV. Toll-like receptors new horizons in sepsis.Current Molecular Medicine,2007,7:522-531.
29. Smirnoval I, Hamblin MT, McBride C, et al., Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans. Genetics,2001,158(4): 1657-1664.
30. Nguyen Thi Hue, Mai Ngoc Lanh, Le Thi Phuong, et al. Toll-Like Receptor 4 (TLR4) and Typhoid Fever in Vietnam. PLoS ONE,2009,4(3):e4800.
31. Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet,2000,25(2):187-191.
32. Lorenz E, Mira JP, Frees KL, et al. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med,2002,162(9): 1028-1032.
33. Barber RC, Chang LY, Arnoldo BD, et al. Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res.20064(4):250-255.
34. Barber RC, Aragaki CC, Rivera-Chavez FA, et al. TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury. J Med Genet,2004 41(11):808-13.
35. Shalhub S, Junker CE, Imahara SD, et al. Variation in the TLR4 gene influences the risk of organ failure and shock postrauma:A cohort study. J Trauma,2009,66(1): 115-122.
36. Agnese DM, Calvano JE, Hahm SJ, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis,2002,186(10):1522-1525.
37. Van der Graaf CA, Netea MG, Morre SA, et al. Toll-like receptor 4 Asp299Gly/Thr399lle polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw,2006,17(1):29-34.
38. Bochud PY, Chien JW, Marr KA, et al. Toll-like receptor 4 polymorphisms and Aspergillosis in stem-cell transplantation. N Engl J Med,2008,359(17): 1766-1777.
39. Kumpf O, Hamann L, Schlag PM, et al. Pre-and postoperative cytokine release after in vitro whole blood lipopolysaccharide stimulation and frequent toll-like receptor 4 polymorphisms. Shock,2006,25(2):123-128.
40. Taudorf S, Krabbe KS, Berg RM, et al. Common studied polymorphisms do not affect plasma cytokine levels upon endotoxin exposure in humans. Clin Exp Immunol,2008,152(1):147-152.
41. Song ZJ, Yin J, Tong CY, et al. Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population. Critical care,2011,15:R12.
42. Duan ZX, Gu W, Zhang LY,et al.Clinical relevance of the TLR4 11367 polymorphism in patients with major trauma. Arch Surg.2009,144 (12):1144-1148.
43. Chen K, Wang YT, Gu W, et al.Functional significance of the Toll-like receptor 4 promoter gene polymorphisms in the Chinese Han population. Crit Care Med. 2010,38(5):1292-1299.
44. Milena Karina Colo Brunialti, Paulo Sergio Martins, Heraclito Barbosa de Carvalho, et.al. TLR2, TLR4, CD14, CD11B, AND CD11C EXPRESSIONS ON MONOCYTES SURFACE AND CYTOKINE PRODUCTION IN PATIENTS WITH SEPSIS, SEVERE SEPSIS, AND SEPTIC SHOCK. SHOCK,2006,25(4):351-357.
45. Armstrong L, Medford AR, Hunter KJ,et,al. Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis. Clin Exp Immunol. 2004,136(2):312-319.
[1]. Alfred Ayala*, Mario Perl, Fabienne Venet. Apoptosis in Sepsis:Mechanisms, Clinical Impact and Potential Therapeutic Targets. Current Pharmaceutical Design, 2008,14:1853-1859.
[2]. Douglas D. Bannerman,* Kristine T. Eiting,? Robert K. Winn,?. FLICE-Like Inhibitory Protein (FLIP) Protects Against Apoptosis and Suppresses NF-_B Activation Induced by Bacterial Lipopolysaccharide. American Journal of Pathology,2004,165(4):1423-1431.
[3]. Knuefermann P, Nemoto S, Misra A, et al. CD14-deficient mice are protected against lipopolysaccharide induced cardiac inflammation and left ventricular dysfunction.Circulation,2002,106:2608-2615.
[4]. Richard S. Hotchkiss* Donald W. Nicholsont. Apoptosis and caspases regulate death and inflammation in sesis. www.nature.com/reviews/immunol,2006,6: 813-822.
[5]. Matute2Bello G, Martin TR. Science review:apop tosis in acute lung injury. Crit Care,2003,5:355-358.
[6]. Ravi Taneja, Jean Parodo, Song Hui Jia. Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity. Crit Care Med,2004,32:1460-1469.
[7]. Evangelos J Giamarellos-Bourboulisl, Christina Routsi2, Diamantis Plachourasl.Early apoptosis of blood monocytes in the septic host:is it a mechanism of protection in the event of septic shock? Critical Care,2006,10:R76.
[8]. A. Antonopoulou,* M. Raftogiannis,*E. J. Giamarellos-Bourboulis, Early apoptosis of blood monocytes is a determinant of survival in experimental sepsis by multi-drug-resistant Pseudomonas aeruginosa. Clinical and Experimental Immunology,2007,149:103-108.
[9]. N. Efstathopoulos,* T. Tsaganos, E. J. Giamarellos-Bourboulis, Early apoptosis of monocytes contributes to the pathogenesis of systemic inflammatory response and of bacterial translocation in an experimental model of multiple trauma. Clinical and Experimental immunology,2006,145:139-146.
[10]. tA. Antonopoulou,* M. Raftogiannis,* E. J. Giamarellos-Bourboulis,* Early apoptosis of blood monocytes is a determinant of survival in experimental sepsis by multi-drug-resistant Pseudomonas aeruginosa?. Clinical and Experimental Immunology,2007,149:103-108.
[11]. Richard S. Hotchkiss, M.D., Andreas Strasser, Ph.D., Jonathan E. McDunn, Ph.D., Cell Death. N Engl J Med,2009,361:1570-83.
[12]. Zhang Z, Schluesener HJ. Mammalian Toll-like receptors:from endogenous ligands to tissue regeneration. Cell Mol Life Sci,2006,63:2901-7.
[13]. Kim HM, Park BS, Kim JI, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell,2007,130(5):906-917.
[14]. Wei Chao. Toll-like receptor signaling:a critical modulator of cell survival and ischemic injury in the heart. Am J Physiol Heart Circ Physiol,2009,296(1): H1-H12.
[15]. Christos I. Maratheftis*, Stavroula Giannouli*, Maria P. Spachidou*,RNA Interference of Interferon Regulatory Factor-1 Gene Expression in THP-1 Cell Line Leads to Toll-Like Receptor-4 Overexpression/Activation As Well As Up-modulation of Annexin-II1. Neoplasia,2007,9(12):1012-1020.
[16]. Monneret G, Debard AL, Venet F, et al. Marked elevation of human circulating CD4_CD25_ regulatory T cells in sepsisinduced immunoparalysis. Crit Care Med, 2003,31:2068-2071.
[17]. Venet F, Pachot A, Debard AL, Human CD4+CD25+regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol,2006,177(9):6540-7.
[18]. Carl De Trez*, Bernard Pajak*, Maryse Brait*, TLR4 and Toll-IL-1 Receptor Domain-Containing Adapter-Inducing IFN-β, but Not MyD88, Regulate Escherichia coli-Induced Dendritic Cell Maturation and Apoptosis In Vivo. J Immunol,2005, 175(2):839-46.
[19]. Ulzma A. Hasan*?, Christophe Caux?, Ivan Perrot§. Cell proliferation and survival induced by Toll-like receptors is antagonized by type I INFs.IFNs. PNAS, 2007,104(19):8047-8052.
[20]. Lombardo E, Alvarez-Barrientos A, Maroto B, TLR4-mediated survival of macrophages is MyD88 dependent and requires TNF-alpha autocrine signalling. J Immunol,2007,178(6):3731-9.
[21]. Klaus Ruckdeschel2,*, Gudrun Pfaffinger*, Rudolf Haase*, Signaling of Apoptosis through TLRs Critically Involves Toll/IL-1 Receptor Domain-Containing Adapter Inducing IFN-β, but Not MyD88, in Bacteria-Infected Murine Macrophagesl. J Immunol,2004,173(5):3320-8.
[22]. Susanne Kirschnek*, Songmin Ying*, Silke F. Fischer*, Phagocytosis-Induced Apoptosis in Macrophages Is Mediated by Up-Regulation and Activation of the Bcl-2 Homology Domain 3-Only Protein Biml. J Immunol,2005,174(2):671-9.
[23]. Stephanie Francois*,?, Jamel El Benna*, Pham M. C. Dang*, Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood:Involvement of the Phosphoinositide 3-Kinase/Akt and NF-KB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad. J Immunol,2005, 174(6):3633-42.
[24]. Luciano Ottonello, Maria Bertolotto, Fabrizio Montecucco*.Delayed apoptosis of human monocytes exposed to immune complexes is reversed by oxaprozin: role of the Akt/IkB kinase/nuclear factor kB pathway. British Journal of Pharmacology,2009,157:294-306.
[2]Nee P.A., Critical care in the emergency department:severe sepsis and septic shock. Emerg Med J,2006.23(9):713-717.
[3]Angus D.C., Linde-Zwirble W.T., Lidicker J., et al., Epidemiology of severe sepsis in the United States:analysis of incidence, outcome, and associated costs of care. Crit Care Med,2001. 29(7):1303-1310.
[4]Abraham E., Laterre P.F., Garbino J., et al., Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock:a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med,2001. 29(3):503-510.
[5]Lopez A., Lorente J.A., Steingrub J., et al., Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88:effect on survival in patients with septic shock. Crit Care Med,2004.32(1):21-30.
[6]Opal S., Laterre P.F., Abraham E., et al., Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis:results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med,2004.32(2):332-341.
[7]Cinel I. and Opal S.M., Molecular biology of inflammation and sepsis:a primer. Crit Care Med, 2009.37(l):291-304.
[8]Teuffel O., Ethier M.C., Beyene J., et al., Association between tumor necrosis factor-alpha promoter -308 A/G polymorphism and susceptibility to sepsis and sepsis mortality:a systematic review and meta-analysis. Crit Care Med,2010.38(1):276-282.
[9]Majetschak M., Obertacke U., Schade F.U., et al., Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma patients. Clin Diagn Lab Immunol, 2002.9(6):1205-1211.
[10]Stanilova S.A., Functional relevance of IL-10 promoter polymorphisms for sepsis development. Crit Care,2010.14(1):119.
[11]Barber R.C., Aragaki C.C., Chang L.Y., et al., CD14-159 C allele is associated with increased risk of mortality after burn injury. Shock,2007.27(3):232-237.
[12]Medzhitov R., Preston-Hurlburt P. and Janeway C.A., Jr., A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature,1997. 388(6640):394-397.
[13]Barreiro L.B., Ben-Ali M., Quach H., et al., Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense. PLoS Genet,2009.5(7):e1000562.
[14]Akira S. and Takeda K., Toll-like receptor signalling. Nat Rev Immunol,2004.4(7):499-511.
[15]Hoshino K., Takeuchi O., Kawai T., et al., Cutting edge:Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide:evidence for TLR4 as the Lps gene product.J Immunol,1999.162(7):3749-3752.
[16]Poltorak A., Smirnova I., He X., et al., Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol Dis,1998.24(3):340-355.
[17]Bochud P.Y., Chien J.W., Marr K.A., et al., Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med,2008.359(17):1766-1777.
[18]Kupcinskas J., Wex T., Bornschein J., et al., Lack of association between gene polymorphisms of Angiotensin converting enzyme, Nod-like receptor 1, Toll-like receptor 4, FAS/FASL and the presence of Helicobacter pylori-induced premalignant gastric lesions and gastric cancer in Caucasians, BMC Med Genet,2011.12:112.
[19]Zhou H., Andonegui G., Wong C.H., et al.. Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. J Immunol,2009. 183(8):5244-5250.
[20]Hu G., Malik A.B. and Minshall R.D., Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation. Crit Care Med,2010.38(1):194-201.
[21]Rumbaut R.E., Bellera R.V., Randhawa J.K., et al., Endotoxin enhances microvascular thrombosis in mouse cremaster venules via a TLR4-dependent, neutrophil-independent mechanism. Am J Physiol Heart Circ Physiol,2006.290(4):H1671-1679.
[22]Zhang G., Han J., Welch E.J., et al., Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol,2009.182(12):7997-8004.
[23]Ferwerda B., McCall M.B., Alonso S., et al., TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans. Proc Natl Acad Sci U S A,2007. 104(42):16645-16650.
[24]Arbour N.C., Lorenz E., Schutte B.C., et al., TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet,2000.25(2):187-191.
[25]Lorenz E., Mira J.P., Frees K.L., et al.. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med,2002.162(9):1028-1032.
[26]Ahrens P., Kattner E., Kohler B., et al., Mutations of genes involved in the innate immune system as predictors of sepsis in very low birth weight infants. Pediatr Res,2004. 55(4):652-656.
[27]Read R.C., Pullin J., Gregory S., et al., A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis,2001. 184(5):640-642.
[28]Agnese D.M., Calvano J.E., Hahm S.J., et al., Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis,2002.186(10):1522-1525.
[29]Smirnova I., Mann N., Dols A., et al., Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci U S A,2003. 100(10):6075-6080.
[30]Feterowski C., Emmanuilidis K., Miethke T., et al., Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis. Immunology,2003. 109(3):426-431.
[31]Van der Graaf C.A., Netea M.G., Morre S.A., et al., Toll-like receptor 4 Asp299Gly/Thr399lle polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw,2006. 17(1):29-34.
[32]Everett B., Cameron B., Li H., et al., Polymorphisms in Toll-like receptors-2 and -4 are not associated with disease manifestations in acute Q fever. Genes Immun,2007.8(8):699-702.
[33]Yuan F.F., Marks K., Wong M., et al., Clinical relevance of TLR2, TLR4, CD14 and FcgammaRIIA gene polymorphisms in Streptococcus pneumoniae infection. Immunol Cell Biol,2008. 86(3):268-270.
[34]Henckaerts L., Nielsen K.R., Steffensen R., et al., Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med,2009. 37(1):192-201, e191-193.
[35]Mensah N.Y., Peterlongo P., Steinherz P., et al., Toll-like receptor 4 polymorphisms and risk of gram-negative bacteremia after allogeneic stem cell transplantation. A prospective pilot study. Biol Blood Marrow Transplant,2009.15(9):1130-1133.
[36]Horcajada J.P., Lozano F., Munoz A., et al., Polymorphic receptors of the innate immune system (MBL/MASP-2 and TLR2/4) and susceptibility to pneumococcal bacteremia in HIV-infected patients:a case-control study. Curr HIV Res,2009.7(2):218-223.
[37]Ozgur T.T., Yel L., Yigit S., et al.. Lack of association between TLR4 polymorphism and severe gram-negative bacterial infection in neonates. Turkish Journal of Medical Sciences,2009. 39(3):423-427.
[38]Kumpf O., Giamarellos-Bourboulis E.J., Koch A., et al., Influence of genetic variations in TLR4 and TIRAP/Mal on the course of sepsis and pneumonia and cytokine release:an observational study in three cohorts. Crit Care,2010.14(3):R103.
[39]Guarner-Argente C., Sanchez E., Vidal S., et al., Toll-like receptor 4 D299G polymorphism and the incidence of infections in cirrhotic patients. Aliment Pharmacol Ther,2010. 31(11):1192-1199.
[40]Carregaro F., Carta A., Cordeiro J.A., et al., Polymorphisms IL10-819 and TLR-2 are potentially associated with sepsis in Brazilian patients. Mem Inst Oswaldo Cruz,2010.105(5):649-656.
[41]Ahmad-Nejad P., Denz C., Zimmer W., et al., The Presence of Functionally Relevant Toll-Like Receptor Polymorphisms Does Not Significantly Correlate with Development or Outcome of Sepsis. Genetic Testing and Molecular Biomarkers,2011.15(9):645-651.
[42]Kajikawa O., Frevert C.W., Lin S.M., et al., Gene expression of Toll-like receptor-2, Toll-like receptor-4, and MD2 is differentially regulated in rabbits with Escherichia coli pneumonia. Gene,2005.344:193-202.
[43]van der Graaf C., Kullberg B.J., Joosten L., et al., Functional consequences of the Asp299Gly Toll-like receptor-4 polymorphism. Cytokine,2005.30(5):264-268.
[44]Schippers E.F., van't Veer C., van Voorden S., et al., IL-10 and toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. Cytokine,2005. 29(5):215-228.
[45]Calvano J.E., Bowers D.J., Coyle S.M., et al., Response to systemic endotoxemia among humans bearing polymorphisms of the Toll-like receptor 4 (hTLR4). Clin Immunol,2006. 121(2):186-190.
[46]Fitzgerald K.A., Palsson-McDermott E.M., Bowie A.G., et al., Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature,2001.413(6851):78-83.
[47]Villar J., Maca-Meyer N., Perez-Mendez L., et al.,Bench-to-bedside review:understanding genetic predisposition to sepsis. Crit Care,2004.8(3):180-189.
[48]Levy M.M., Fink M.P., Marshall J.C., et al.,2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med,2003.31(4):1250-1256.
[49]Ritchie M.D., Hahn LW. and Moore J.H., Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol,2003.24(2):150-157.
[50]Moore J.H., Gilbert J.C., Tsai C.T., et al., A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol,2006.241(2):252-261.
[51]Kimman T.G., Banus S., Reijmerink N., et al., Association of interacting genes in the toll-like receptor signaling pathway and the antibody response to pertussis vaccination. PLoS One, 2008.3(11):e3665.
[52]Dhiman N., Ovsyannikova I.G., Vierkant R.A., et al., Associations between SNPs in toll-like receptors and related intracellular signaling molecules and immune responses to measles vaccine:preliminary results. Vaccine,2008.26(14):1731-1736.
[53]Song Z., Yin J., Yao C., et al., Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population. Crit Care,2011.15(1):R12.
[54]Abu-Maziad A., Schaa K., Bell E.F., et al., Role of polymorphic variants as genetic modulators of infection in neonatal sepsis. Pediatr Res,2010.68(4)323-329.
[55]Barber R.C., Chang L.Y., Arnoldo B.D., et al., Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res,2006.4(4):250-255.
[56]Vogel S.N., Fitzgerald K.A. and Fenton M.J., TLRs:differential adapter utilization by toll-like receptors mediates TLR-specific patterns of gene expression. Mol Interv,2003.3(8):466-477.
[57]Hawn T.R., Dunstan S.J., Thwaites G.E., et al., A polymorphism in Toll-interleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. J Infect Dis,2006.194(8):1127-1134.
[58]Khor C.C., Chapman S.J., Vannberg F.O., et al., A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet,2007.39(4):523-528.
[59]Scott L.J., Mohlke K.L, Bonnycastle L.L., et al., A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science,2007. 316(5829):1341-1345.
[60]Nagai Y, Akashi S., Nagafuku M., et al., Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol,2002.3(7):667-672.
[61]Schromm A.B., Lien E., Henneke P., et al., Molecular genetic analysis of an endotoxin nonresponder mutant cell line:a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. J Exp Med,2001.194(1):79-88.
[62]Smit L.A., Heederik D., Doekes G., et al., Endotoxin exposure, CD14 and wheeze among farmers:a gene-environment interaction. Occup Environ Med,2011.
[63]Nguyen T.H., Mai N.L., Le T.P., et al., Toll-like receptor 4 (TLR4) and typhoid fever in Vietnam. PLoS One,2009.4(3):e4800.
[64]Duan Z.X., Gu W., Zhang L.Y., et al., Clinical relevance of the TLR4 11367 polymorphism in patients with major trauma. Arch Surg,2009.144(12):1144-1148.
[65]Chen K., Wang Y.T., Gu W., et al., Functional significance of the Toll-like receptor 4 promoter gene polymorphisms in the Chinese Han population. Crit Care Med,2010.38(5):1292-1299.
[66]Hishida A., Matsuo K., Goto Y, et al., Toll-like receptor 4+3725 G/C polymorphism, Helicobacter pylori seropositivity, and the risk of gastric atrophy and gastric cancer in Japanese. Helicobacter,2009.14(1):47-53.
[67]Zhou L., Wei B., Xing C., et al., Polymorphism in 3'-untranslated region of toll-like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantation. Transpl Infect Dis,2011.13(3):250-258.
[68]Duan Z.X., Zhu P.F., Dong H., et al., Functional significance of the TLR4/11367 polymorphism identified in Chinese Han population. Shock,2007.28(2):160-164.
[69]Tanguay R.L.and Gallie D.R., Translational efficiency is regulated by the length of the 3' untranslated region. Mol Cell Biol,1996.16(1):146-156.
[70]Penders J., Thijs C., Mommers M., et al., Host-microbial interactions in childhood atopy: toll-like receptor 4 (TLR4), CD14, and fecal Escherichia coli. J Allergy Clin Immunol,2010. 125(1):231-236 e231-235.
[71]Ferrero E., Jiao D., Tsuberi B.Z., et al., Transgenic mice expressing human CD14 are hypersensitive to lipopolysaccharide. Proc Natl Acad Sci U S A,1993.90(6):2380-2384.
[72]Carrillo E.H., Gordon L., Goode E., et al., Early elevation of soluble CD14 may help identify trauma patients at high risk for infection. J Trauma,2001.50(5):810-816.
[73]Burgmann H., Winkler S., Locker G.J., et al., Increased serum concentration of soluble CD14 is a prognostic marker in gram-positive sepsis. Clin Immunol Immunopathol,1996.80(3 Pt 1):307-310.
[74]Hubacek J.A., Stuber F., Frohlich D., et al., The common functional C(-159)T polymorphism within the promoter region of the lipopolysaccharide receptor CD14 is not associated with sepsis development or mortality. Genes Immun,2000. 1(6):405-407.
[75]Gu W., Dong H., Jiang D.P., et al., Functional significance of CD14 promoter polymorphisms and their clinical relevance in a Chinese Han population. Crit Care Med,2008. 36(8):2274-2280.
[76]Lin J., Yao Y.M., Yu Y., et al., Effects of CD14-159 C/T polymorphism on CD14 expression and the balance between proinflammatory and anti-inflammatory cytokines in whole blood culture. Shock,2007.28(2):148-153.
[77]de Aguiar B.B., Girardi I., Paskulin D.D., et al., CD14 expression in the first 24h of sepsis:effect of-260C>T CD14 SNP. Immunol Invest,2008.37(8):752-769.
[78]Kudsk K.A., Tolley E.A., DeWitt R.C., et al., Preoperative albumin and surgical site identify surgical risk for major postoperative complications. JPEN J Parenter Enteral Nutr,2003. 27(1):1-9.
[79]Azim K., McManus R., Brophy K., et al., Genetic polymorphisms and the risk of infection following esophagectomy. positive association with TNF-alpha gene -308 genotype. Ann Surg, 2007.246(1):122-128.
[80]Rodriguez F., Barrera L., De La Rosa G., et al., The epidemiology of sepsis in Colombia:a prospective multicenter cohort study in ten university hospitals. Crit Care Med,2011. 39(7):1675-1682.
[81]Jansky L., Reymanova P. and Kopecky J., Dynamics of cytokine production in human peripheral blood mononuclear cells stimulated by LPS or infected by Borrelia. Physiol Res, 2003.52(5):593-598.
[82]Lantos J., Foldi V., Roth E., et al., Burn trauma induces early HMGB1 release in patients:its correlation with cytokines. Shock,2010.33(6):562-567.
1. Medzhitov R, Preston-Hurlburt P, Janeway Jr CA. A human homologue of the Drosophila Toll proteins signals activation of adaptive immunity. Nature 1997; 388:394-7.
2. Sachidanandam, R., D. Weissman, S. C. Schmidt, J. M. et al. International SNP Map Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature,2001,409:928-33.
3. Janeway, C.A., Medzhltov, R. Innate immune recognition. Annu Rev Immunol, 2002,20:197-216.
4. Netea, M. G., C. A. Van Der Graaf, A. G. Vonk, et al. The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J. Infect. Dis.2002,185:1483-9.
5. Poltorak, A., X. He, I. Smirnova, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice:mutations in Tlr4 gene. Science,1998,282:2085-8.
6. Hoshino K, Takeuchi 0, Kawai T, et al. Cutting edge:Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide:evidence for TLR4 as the Lps gene product. J Immunol,1999,162(7):3749-3752.
7. Zhou H, Andonegui G, Wong CH, et al. Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. J Immunol.2009,183(8):5244-50.
8. Hu G, Malik AB, Minshall RD. Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation. Crit Care Med.2010,38(1):194-201.
9. Zhang G, Han J, Welch EJ, Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol.2009,182(12):7997-8004.
10. Rumbaut RE, Bellera RV, Randhawa JK, Endotoxin enhances microvascular thrombosis in mouse cremaster venules via a TLR4-dependent, neutrophil-independent mechanism. Am J Physiol Heart Circ Physiol.2006, 290(4):H1671-9.
11. Rodriguez S, Chora A, Goumnerov B,Dysfunctional expansion of hematopoietic stem cells and block of myeloid differentiation in lethal sepsis. Blood.2009, 114(19):4064-76.
12. T. Roger, C. Froidevaux, D. Le Roy, et al., Protection from lethal Gram-negative bacterial sepsis by targeting Toll-like receptor 4. Proceedings of the National Academy of Sciences of the United States of America,2009,106(7): 2348-2352.
13. P. Groβ, K. Brandl, C. Dierkes, et al., Lipopolysaccharide-Trap-Fc, a multifunctional agent to battle gram-negative bacteria. Infection and Immunity,2009,77(7): 2925-2931.
14. Hong, Z. Jiang, W. Liangxi, et al., Chloroquine protects mice from challenge with CpG ODN and LPS by decreasing proinflammatory cytokine release. International Immunopharmacology,2004,4(2):223-234.
15. H. Methe, J.-O. Kim, S. Kofler, M. et al., Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Arteriosclerosis, Thrombosis, and Vascular Biology,2005,25(7):1439-1445.
16. Yu, D. Shao, J. Liu, J. et al. Effects of ketamine on levels of cytokines, NF-kB and TLRs in rat intestine during CLP-induced sepsis. International Immunopharmacology,2007,7(8):1076-1082.
17. L.-H. Guo, H. J. Schluesener, The innate immunity of the central nervous system in chronic pain:the role of Toll-like receptors. Cellular and Molecular Life Sciences, 2007,64(9):1128-1136.
18. Sackesen, C., C. Karaaslan, O. Keskin, N. et al. The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy,2005,60:1485-92.
19. Laine, M. L., S. A. Morre, L. S. Murillo, et al. CD14 and TLR4 gene polymorphisms in adult periodontitis. J. Dent. Res.2005,84:1042-1046.
20. Jeyaseelan, S., H. W. Chu, S. K. Young, et al. Distinct roles of pattern recognition receptors CD14 and Toll-like receptor 4 in acute lung injury. Infect. Immun.2005, 73:1754-63.
21. Chen, Y. C., E. Giovannucci, R. Lazarus, et al. Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res.2005, 65:11771-11778.
22. Kiechl, S., E. Lorenz, M. Reindl, C. J., et al. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med.2002,347:185-192.
23. Heesen, M., M. Wessiepe, D. Kunz, K. et al. Rapid and reliable genotyping for the Toll-like receptor 4 A896G polymorphism using fluorescence-labeled hybridization probes in a real-time polymerase chain reaction assay. Clin. Chim. Acta,2003,333:47-49.
24. Hawn TR, Scholes D, Li SS, et al. Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women.PLoS One.2009 Jun 22; 4(6):e5990.
25. Dahmer, M. K., A. Randolph, S. Vitali, et al. Genetic polymorphisms in sepsis. Pediatr. Crit. Care Me.2005,6(3 Suppl):S61-73.
26. Guo, Q. S., B. Xia, Y. Jiang, et al. Polymorphisms of CD14 gene and TLR4 gene are not associated with ulcerative colitis in Chinese patients. Postgrad. Med. J.2005, 81:526-529.
27. Lorenz, E., K. L. Frees, D. A. Schwartz. Determination of the TLR4 genotype using allele-specific PCR. Biotechniques,2001,31:22-24.
28. Saturnino SF, Andrade MV. Toll-like receptors new horizons in sepsis.Current Molecular Medicine,2007,7:522-531.
29. Smirnoval I, Hamblin MT, McBride C, et al., Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans. Genetics,2001,158(4): 1657-1664.
30. Nguyen Thi Hue, Mai Ngoc Lanh, Le Thi Phuong, et al. Toll-Like Receptor 4 (TLR4) and Typhoid Fever in Vietnam. PLoS ONE,2009,4(3):e4800.
31. Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet,2000,25(2):187-191.
32. Lorenz E, Mira JP, Frees KL, et al. Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med,2002,162(9): 1028-1032.
33. Barber RC, Chang LY, Arnoldo BD, et al. Innate immunity SNPs are associated with risk for severe sepsis after burn injury. Clin Med Res.20064(4):250-255.
34. Barber RC, Aragaki CC, Rivera-Chavez FA, et al. TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury. J Med Genet,2004 41(11):808-13.
35. Shalhub S, Junker CE, Imahara SD, et al. Variation in the TLR4 gene influences the risk of organ failure and shock postrauma:A cohort study. J Trauma,2009,66(1): 115-122.
36. Agnese DM, Calvano JE, Hahm SJ, et al. Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis,2002,186(10):1522-1525.
37. Van der Graaf CA, Netea MG, Morre SA, et al. Toll-like receptor 4 Asp299Gly/Thr399lle polymorphisms are a risk factor for Candida bloodstream infection. Eur Cytokine Netw,2006,17(1):29-34.
38. Bochud PY, Chien JW, Marr KA, et al. Toll-like receptor 4 polymorphisms and Aspergillosis in stem-cell transplantation. N Engl J Med,2008,359(17): 1766-1777.
39. Kumpf O, Hamann L, Schlag PM, et al. Pre-and postoperative cytokine release after in vitro whole blood lipopolysaccharide stimulation and frequent toll-like receptor 4 polymorphisms. Shock,2006,25(2):123-128.
40. Taudorf S, Krabbe KS, Berg RM, et al. Common studied polymorphisms do not affect plasma cytokine levels upon endotoxin exposure in humans. Clin Exp Immunol,2008,152(1):147-152.
41. Song ZJ, Yin J, Tong CY, et al. Variants in the Toll-interacting protein gene are associated with susceptibility to sepsis in the Chinese Han population. Critical care,2011,15:R12.
42. Duan ZX, Gu W, Zhang LY,et al.Clinical relevance of the TLR4 11367 polymorphism in patients with major trauma. Arch Surg.2009,144 (12):1144-1148.
43. Chen K, Wang YT, Gu W, et al.Functional significance of the Toll-like receptor 4 promoter gene polymorphisms in the Chinese Han population. Crit Care Med. 2010,38(5):1292-1299.
44. Milena Karina Colo Brunialti, Paulo Sergio Martins, Heraclito Barbosa de Carvalho, et.al. TLR2, TLR4, CD14, CD11B, AND CD11C EXPRESSIONS ON MONOCYTES SURFACE AND CYTOKINE PRODUCTION IN PATIENTS WITH SEPSIS, SEVERE SEPSIS, AND SEPTIC SHOCK. SHOCK,2006,25(4):351-357.
45. Armstrong L, Medford AR, Hunter KJ,et,al. Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis. Clin Exp Immunol. 2004,136(2):312-319.
[1]. Alfred Ayala*, Mario Perl, Fabienne Venet. Apoptosis in Sepsis:Mechanisms, Clinical Impact and Potential Therapeutic Targets. Current Pharmaceutical Design, 2008,14:1853-1859.
[2]. Douglas D. Bannerman,* Kristine T. Eiting,? Robert K. Winn,?. FLICE-Like Inhibitory Protein (FLIP) Protects Against Apoptosis and Suppresses NF-_B Activation Induced by Bacterial Lipopolysaccharide. American Journal of Pathology,2004,165(4):1423-1431.
[3]. Knuefermann P, Nemoto S, Misra A, et al. CD14-deficient mice are protected against lipopolysaccharide induced cardiac inflammation and left ventricular dysfunction.Circulation,2002,106:2608-2615.
[4]. Richard S. Hotchkiss* Donald W. Nicholsont. Apoptosis and caspases regulate death and inflammation in sesis. www.nature.com/reviews/immunol,2006,6: 813-822.
[5]. Matute2Bello G, Martin TR. Science review:apop tosis in acute lung injury. Crit Care,2003,5:355-358.
[6]. Ravi Taneja, Jean Parodo, Song Hui Jia. Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity. Crit Care Med,2004,32:1460-1469.
[7]. Evangelos J Giamarellos-Bourboulisl, Christina Routsi2, Diamantis Plachourasl.Early apoptosis of blood monocytes in the septic host:is it a mechanism of protection in the event of septic shock? Critical Care,2006,10:R76.
[8]. A. Antonopoulou,* M. Raftogiannis,*E. J. Giamarellos-Bourboulis, Early apoptosis of blood monocytes is a determinant of survival in experimental sepsis by multi-drug-resistant Pseudomonas aeruginosa. Clinical and Experimental Immunology,2007,149:103-108.
[9]. N. Efstathopoulos,* T. Tsaganos, E. J. Giamarellos-Bourboulis, Early apoptosis of monocytes contributes to the pathogenesis of systemic inflammatory response and of bacterial translocation in an experimental model of multiple trauma. Clinical and Experimental immunology,2006,145:139-146.
[10]. tA. Antonopoulou,* M. Raftogiannis,* E. J. Giamarellos-Bourboulis,* Early apoptosis of blood monocytes is a determinant of survival in experimental sepsis by multi-drug-resistant Pseudomonas aeruginosa?. Clinical and Experimental Immunology,2007,149:103-108.
[11]. Richard S. Hotchkiss, M.D., Andreas Strasser, Ph.D., Jonathan E. McDunn, Ph.D., Cell Death. N Engl J Med,2009,361:1570-83.
[12]. Zhang Z, Schluesener HJ. Mammalian Toll-like receptors:from endogenous ligands to tissue regeneration. Cell Mol Life Sci,2006,63:2901-7.
[13]. Kim HM, Park BS, Kim JI, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell,2007,130(5):906-917.
[14]. Wei Chao. Toll-like receptor signaling:a critical modulator of cell survival and ischemic injury in the heart. Am J Physiol Heart Circ Physiol,2009,296(1): H1-H12.
[15]. Christos I. Maratheftis*, Stavroula Giannouli*, Maria P. Spachidou*,RNA Interference of Interferon Regulatory Factor-1 Gene Expression in THP-1 Cell Line Leads to Toll-Like Receptor-4 Overexpression/Activation As Well As Up-modulation of Annexin-II1. Neoplasia,2007,9(12):1012-1020.
[16]. Monneret G, Debard AL, Venet F, et al. Marked elevation of human circulating CD4_CD25_ regulatory T cells in sepsisinduced immunoparalysis. Crit Care Med, 2003,31:2068-2071.
[17]. Venet F, Pachot A, Debard AL, Human CD4+CD25+regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol,2006,177(9):6540-7.
[18]. Carl De Trez*, Bernard Pajak*, Maryse Brait*, TLR4 and Toll-IL-1 Receptor Domain-Containing Adapter-Inducing IFN-β, but Not MyD88, Regulate Escherichia coli-Induced Dendritic Cell Maturation and Apoptosis In Vivo. J Immunol,2005, 175(2):839-46.
[19]. Ulzma A. Hasan*?, Christophe Caux?, Ivan Perrot§. Cell proliferation and survival induced by Toll-like receptors is antagonized by type I INFs.IFNs. PNAS, 2007,104(19):8047-8052.
[20]. Lombardo E, Alvarez-Barrientos A, Maroto B, TLR4-mediated survival of macrophages is MyD88 dependent and requires TNF-alpha autocrine signalling. J Immunol,2007,178(6):3731-9.
[21]. Klaus Ruckdeschel2,*, Gudrun Pfaffinger*, Rudolf Haase*, Signaling of Apoptosis through TLRs Critically Involves Toll/IL-1 Receptor Domain-Containing Adapter Inducing IFN-β, but Not MyD88, in Bacteria-Infected Murine Macrophagesl. J Immunol,2004,173(5):3320-8.
[22]. Susanne Kirschnek*, Songmin Ying*, Silke F. Fischer*, Phagocytosis-Induced Apoptosis in Macrophages Is Mediated by Up-Regulation and Activation of the Bcl-2 Homology Domain 3-Only Protein Biml. J Immunol,2005,174(2):671-9.
[23]. Stephanie Francois*,?, Jamel El Benna*, Pham M. C. Dang*, Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood:Involvement of the Phosphoinositide 3-Kinase/Akt and NF-KB Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad. J Immunol,2005, 174(6):3633-42.
[24]. Luciano Ottonello, Maria Bertolotto, Fabrizio Montecucco*.Delayed apoptosis of human monocytes exposed to immune complexes is reversed by oxaprozin: role of the Akt/IkB kinase/nuclear factor kB pathway. British Journal of Pharmacology,2009,157:294-306.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |