Toll样受体2在脓毒症所致心功能障碍及高致死率中的作用研究
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摘要
研究目的：脓毒症(sepsis)是在感染情况下发生的全身性免疫反应综合征(systemic inflammatory response syndrome, SIRS),致死率逐年增加,目前认为其发生的根本原因在于机体过度释放细胞因子和炎性介质导致炎症反应失控和免疫机能紊乱。Toll样受体是一类表达于细胞膜上与细胞识别有关的受体家族,作为天然免疫的重要组成部分,Toll样受体是抵御外来微生物感染的第一道防线,并与心脏疾病的发生发展密切相关。心功能障碍是严重感染性脓毒症的主要特征之一,早期诊断脓毒症所致心功能障碍对控制疾病,防止病情恶化有重要意义。应变率(strain rate, SR)成像是近年来超声领域发展的新技术,能较敏感的检测细微心肌收缩力变化。由于脓毒症所致心肌功能障碍的评价及其潜在的信号转导机制尚不完全明确,故本研究旨在验证以下假设：1)应变率成像能够敏感、准确的评价小鼠腹膜炎感染所致脓毒症心肌功能障碍；2)Toll样受体2(Toll-like receptor 2,TLR2)在脓毒症所致心功能障碍、全身炎症反应及高致死率中起关键作用；3)补体因子B是TLRs信号通路下游潜在的关键效应分子。
研究方法及结果：本研究应用盲肠结扎穿孔术(cecum ligation and puncture, CLP)诱导小鼠腹膜炎感染所致脓毒症模型,从不同角度1)在体超声心动图；2)离体心脏灌流；及3)心肌细胞水平,全面评价脓毒症所致心功能障碍。与传统超声心动图指标左室短轴缩短率(fractionshortening, FS)相比,心肌应变率分析能更敏感的检测脓毒症所致细微心肌功能的改变。通过对脓毒症心功能及死亡率的观察,本研究发现TLR2基因敲除(TLR2 KO)小鼠的心功能与野生型(wide type, WT)小鼠相比明显改善,其生存率也明显提高。进一步检测血清中炎症因子产生及腹腔中性粒细胞迁移功能,本研究发现TLR2KO小鼠血清IL-6、TNFα水平明显降低,中性粒细胞迁移至感染灶的功能增强,推测与其心功能受损的减轻,生存率改善有一定关系。为了研究骨髓和实质脏器组织表达的TLR2对脓毒症引起的心功能紊乱的作用,本研究构建了嵌合体小鼠。将TLR2KO小鼠骨髓细胞移植到经致死量放射线照射后的WT小鼠体内构建嵌合体KO→WT小鼠,嵌合体小鼠心脏及其它实质性脏器基因型中存在TLR2基因的表达而骨髓细胞来源的造血细胞如中性粒细胞、巨噬细胞等则无TLR2基因的表达。本研究发现在脓毒症所致心功能损伤,炎症因子产生,中性粒细胞迁移及生存率改善方面,嵌合体KO→WT小鼠与对照组WT→WT相比并无明显优势。此外本研究还发现脓毒症条件下,或激动剂激活TLR2信号通路均可上调补体替代途径中的关键因子---补体因子B在心脏组织及血清中的表达。
结论：以上研究结果提示：1)心肌应变率(SR)分析能早期敏感的评价脓毒症所致心肌功能障碍,为评价小鼠脓毒症所致心功能障碍提供简单、无创的评价方法；2)TLR2信号通路的激活,尤其是心脏及其它实质性脏器中的TLR2信号通路,在介导小鼠脓毒症模型诱导的心功能障碍、全身炎症反应及高致死率中起重要作用；3)补体因子B是TLR2介导的脓毒症所致心功能障碍下游潜在的关键效应分子。
Objectives:Sepsis is a systemic inflammatory response syndrome that occurs during infection and its induced mortality increased annually. To date, the pathophysiology of sepsis is considered to be the over activation of amounts of cytokine production and immune maladjustment. Toll-like receptors (TLRs) family are Pattern-recognition receptors (PRRs) initiate innate immunity through pathogen recognition, playing an important role in innate immunity, reflecting the first line of host defense against pathogen invasion. Recently, TLRs were demonstrated to be related to the development of cardiac disease. Strain rate (SR) imaging is a new developed technique which had been widely used to assess the ventricular contractility in cardiac resynchronization therapy patients. However little study about its use in detection of sepsis induced cardiac dysfunction in mouse model. Septic cardiomyopathy is a main feature of severe sepsis and contributes to its high mortality. Yet our understanding of the signaling mechanisms leading to septic cardiomyopathy is incomplete. The present study was to test the hypotheses that 1) Strain rate derived from Tissue Doppler Imaging can sensitively assess septic cardiac dysfunction in mouse model.2) Toll-like receptor 2 (TLR2) signaling is critical for cardiac dysfunction and high mortality in mice with severe polymicrobial sepsis.3) Complement factor B (cfB) is a critical downstream effector molecular of TLRs.
Methods and Results:Cucem ligation and puncture (CLP) method was used to induce experimental polymicrobial sepsis in mice.24hours after CLP surgery, all mice were represented with cardiac dysfunction assessed by in vivo echocardiography---strain rate analysis, ex vivo isolated heart functional measurement and in vitro sarcomere shortening detection in adult mouse cardiomyocyte. Strain rate was identified as a sensitive method to evaluate CLP induced cardiac dysfunction. Compared to wild type (WT) mice subjected to sepsis, TLR2-/- mice had dramatically improved cardiac function after sepsis as demonstrated by in vivo serial echocardiography, better preserved left ventricular (LV) function in isolated heart, and improved sarcomere shortening in adult cardiomyocytes. There was also a significant survival benefit in TLR2-/-mice compared to WT mice. These favorable outcomes in TLR2-/-mice were associated with attenuated serum IL-6 and TNFa levels and enhanced neutrophil migratory function. The chimeric KO→WT mice, which completely lacked TLR2 gene expression by their bone marrow-derived hematopoietic cells but maintained normal TLR2 expression in the heart and other parenchymal tissues, were not protected from septic injury, exhibiting similar cytokine production, impairment of cardiac function, and mortality compared with the chimeric WT→WT control mice. Finally, the preliminary data suggest that complement factor B, a key component of alternative pathway, was significantly increase in the heart and in plasma in response to TLR2 activation and during polymicrobial sepsis.
Conclusions:These studies suggest that:1) Strain rate was a sensitive and noninvasive method to assess CLP induced septic cardiomyopathy in mouse.2) TLR2 signaling, most likely that of the heart and other parenchymal tissues, plays a critical role in mediating cardiomyopathy, deleterious inflammation, and high mortality during polymicrobial sepsis. 3) cfB is likely a downstream effector of the TLR2-mediated cardiac dysfunction during polymicrobial sepsis.
研究方法及结果：本研究应用盲肠结扎穿孔术(cecum ligation and puncture, CLP)诱导小鼠腹膜炎感染所致脓毒症模型,从不同角度1)在体超声心动图；2)离体心脏灌流；及3)心肌细胞水平,全面评价脓毒症所致心功能障碍。与传统超声心动图指标左室短轴缩短率(fractionshortening, FS)相比,心肌应变率分析能更敏感的检测脓毒症所致细微心肌功能的改变。通过对脓毒症心功能及死亡率的观察,本研究发现TLR2基因敲除(TLR2 KO)小鼠的心功能与野生型(wide type, WT)小鼠相比明显改善,其生存率也明显提高。进一步检测血清中炎症因子产生及腹腔中性粒细胞迁移功能,本研究发现TLR2KO小鼠血清IL-6、TNFα水平明显降低,中性粒细胞迁移至感染灶的功能增强,推测与其心功能受损的减轻,生存率改善有一定关系。为了研究骨髓和实质脏器组织表达的TLR2对脓毒症引起的心功能紊乱的作用,本研究构建了嵌合体小鼠。将TLR2KO小鼠骨髓细胞移植到经致死量放射线照射后的WT小鼠体内构建嵌合体KO→WT小鼠,嵌合体小鼠心脏及其它实质性脏器基因型中存在TLR2基因的表达而骨髓细胞来源的造血细胞如中性粒细胞、巨噬细胞等则无TLR2基因的表达。本研究发现在脓毒症所致心功能损伤,炎症因子产生,中性粒细胞迁移及生存率改善方面,嵌合体KO→WT小鼠与对照组WT→WT相比并无明显优势。此外本研究还发现脓毒症条件下,或激动剂激活TLR2信号通路均可上调补体替代途径中的关键因子---补体因子B在心脏组织及血清中的表达。
结论：以上研究结果提示：1)心肌应变率(SR)分析能早期敏感的评价脓毒症所致心肌功能障碍,为评价小鼠脓毒症所致心功能障碍提供简单、无创的评价方法；2)TLR2信号通路的激活,尤其是心脏及其它实质性脏器中的TLR2信号通路,在介导小鼠脓毒症模型诱导的心功能障碍、全身炎症反应及高致死率中起重要作用；3)补体因子B是TLR2介导的脓毒症所致心功能障碍下游潜在的关键效应分子。
Objectives:Sepsis is a systemic inflammatory response syndrome that occurs during infection and its induced mortality increased annually. To date, the pathophysiology of sepsis is considered to be the over activation of amounts of cytokine production and immune maladjustment. Toll-like receptors (TLRs) family are Pattern-recognition receptors (PRRs) initiate innate immunity through pathogen recognition, playing an important role in innate immunity, reflecting the first line of host defense against pathogen invasion. Recently, TLRs were demonstrated to be related to the development of cardiac disease. Strain rate (SR) imaging is a new developed technique which had been widely used to assess the ventricular contractility in cardiac resynchronization therapy patients. However little study about its use in detection of sepsis induced cardiac dysfunction in mouse model. Septic cardiomyopathy is a main feature of severe sepsis and contributes to its high mortality. Yet our understanding of the signaling mechanisms leading to septic cardiomyopathy is incomplete. The present study was to test the hypotheses that 1) Strain rate derived from Tissue Doppler Imaging can sensitively assess septic cardiac dysfunction in mouse model.2) Toll-like receptor 2 (TLR2) signaling is critical for cardiac dysfunction and high mortality in mice with severe polymicrobial sepsis.3) Complement factor B (cfB) is a critical downstream effector molecular of TLRs.
Methods and Results:Cucem ligation and puncture (CLP) method was used to induce experimental polymicrobial sepsis in mice.24hours after CLP surgery, all mice were represented with cardiac dysfunction assessed by in vivo echocardiography---strain rate analysis, ex vivo isolated heart functional measurement and in vitro sarcomere shortening detection in adult mouse cardiomyocyte. Strain rate was identified as a sensitive method to evaluate CLP induced cardiac dysfunction. Compared to wild type (WT) mice subjected to sepsis, TLR2-/- mice had dramatically improved cardiac function after sepsis as demonstrated by in vivo serial echocardiography, better preserved left ventricular (LV) function in isolated heart, and improved sarcomere shortening in adult cardiomyocytes. There was also a significant survival benefit in TLR2-/-mice compared to WT mice. These favorable outcomes in TLR2-/-mice were associated with attenuated serum IL-6 and TNFa levels and enhanced neutrophil migratory function. The chimeric KO→WT mice, which completely lacked TLR2 gene expression by their bone marrow-derived hematopoietic cells but maintained normal TLR2 expression in the heart and other parenchymal tissues, were not protected from septic injury, exhibiting similar cytokine production, impairment of cardiac function, and mortality compared with the chimeric WT→WT control mice. Finally, the preliminary data suggest that complement factor B, a key component of alternative pathway, was significantly increase in the heart and in plasma in response to TLR2 activation and during polymicrobial sepsis.
Conclusions:These studies suggest that:1) Strain rate was a sensitive and noninvasive method to assess CLP induced septic cardiomyopathy in mouse.2) TLR2 signaling, most likely that of the heart and other parenchymal tissues, plays a critical role in mediating cardiomyopathy, deleterious inflammation, and high mortality during polymicrobial sepsis. 3) cfB is likely a downstream effector of the TLR2-mediated cardiac dysfunction during polymicrobial sepsis.
引文
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1. Angus, D.C., Linde-Zwirble, W.T., Lidicker, J., Clermont, G., Carcillo, J., and Pinsky, M.R.2001. Epidemiology of severe sepsis in the United States:analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303-1310.
2. Hotchkiss, R.S., and Karl, I.E.2003. The pathophysiology and treatment of sepsis. N Engl J Med 348:138-150.
3. Parrillo, J.E.1993. Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471-1477.
4. Flierl, M.A., Rittirsch, D., Huber-Lang, M.S., Sarma, J.V., and Ward, P.A.2008. Molecular events in the cardiomyopathy of sepsis. Mol Med 14:327-336.
5. Alves-Filho, J.C., Freitas, A., Souto, F.O., Spiller, F., Paula-Neto, H., Silva, J.S., Gazzinelli, R.T., Teixeira, M.M., Ferreira, S.H., and Cunha, F.Q.2009. Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis. Proc Natl Acad Sci USA 106:4018-4023.
6. Alves-Filho, J.C., de Freitas, A., Russo, M., and Cunha, F.Q.2006. Toll-like receptor 4 signaling leads to neutrophil migration impairment in polymicrobial sepsis. Crit Care Med 34:461-470.
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