Toll-like receptor 3 plays a central role in cardiac dysfunction during polymicrobial sepsis

被引:58
作者
Gao, Ming [1 ]
Ha, Tuanzhu [1 ]
Zhang, Xia [1 ]
Liu, Li [4 ]
Wang, Xiaohui [1 ]
Kelley, Jim [2 ]
Singh, Krishna [3 ]
Kao, Race [1 ]
Gao, Xiang [5 ]
Williams, David [1 ]
Li, Chuanfu [1 ]
机构
[1] E Tennessee State Univ, James H Quillen Coll Med, Dept Surg, Johnson City, TN 37614 USA
[2] E Tennessee State Univ, James H Quillen Coll Med, Dept Internal Med, Johnson City, TN 37614 USA
[3] E Tennessee State Univ, James H Quillen Coll Med, Dept Physiol, Johnson City, TN 37614 USA
[4] Nanjing Med Univ, Affiliated Hosp 1, Dept Geriatr, Nanjing, Jiangsu, Peoples R China
[5] Nanjing Univ, Anim Model Res Ctr, Nanjing, Jiangsu, Peoples R China
关键词
apoptosis; cardiac function; neutrophils; sepsis; Toll-like receptor 3; NUCLEAR FACTOR INTERLEUKIN-6; FACTOR-KAPPA-B; EARLY ACTIVATION; ISCHAEMIA/REPERFUSION INJURY; EXPRESSION; LIGANDS; INNATE; MYOCARDIUM; MODULATION; MECHANISMS;
D O I
10.1097/CCM.0b013e3182535aeb
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Objective: To determine the role of Toll-like receptor 3 in cardiac dysfunction during polymicrobial sepsis. Design: Controlled animal study. Setting: University research laboratory. Subjects: Male C57BL/6, wild-type, Toll-like receptor 3(-/-). Intervention: Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. Toll-like receptors (TLRs) play a critical role in the pathophysiology of sepsis/septic shock. TLR3 is located in intracellular endosomes, and recognizes double-stranded RNA. This study examined the role of TLR3 in cardiac dysfunction following cecal ligation and puncture (CLP)-induced sepsis. TLR3 knockout (TLR3(-/-), n = 12) and age-matched wild-type (n = 12) mice were subjected to CLP. Cardiac function was measured by echocardiography before and 6 hrs after CLP. Measurements and Main Results: CLP resulted in significant cardiac dysfunction as evidenced by decreased ejection fraction by 25.7% and fractional shortening by 29.8%, respectively. However, TLR3(-/-) mice showed a maintenance of cardiac function at pre-CLP levels. Wild-type mice showed 50% mortality at 58 hrs and 100% mortality at 154 hrs after CLP. In striking contrast, 70% of TLR3(-/-) mice survived indefinitely, that is, >200 hrs. TLR3 deficiency significantly decreased CLP-induced cardiac-myocyte apoptosis and attenuated CLP-induced Fas and Fas ligand expression in the myocardium. CLP-activation of TLR4-mediated nuclear factor-kappa B and Toll/IL-1 receptor-domain-containing adapter-inducing interferon-beta-dependant interferon signaling pathways was prevented by TLR3 deficiency. In addition, CLP-increased vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression, and neutrophil and macrophage sequestration in the myocardium were also attenuated in septic TLR3(-/-) mice. More significantly, adoptive transfer of wild-type bone-marrow stromal cells to TLR3(-/-) mice abolished the cardioprotective effect in sepsis. Conclusions: These data indicate that TLR3 plays a deleterious role in mediating cardiac dysfunction in sepsis. Thus, modulation of the TLR3 activity may be useful in preventing cardiac dysfunction in sepsis. (Crit Care Med 2012; 40:2390-2399)
引用
收藏
页码:2390 / 2399
页数:10
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