Toll-like receptor 3 plays a central role in cardiac dysfunction during polymicrobial sepsis.
Toll-like receptor 3 plays a central role in cardiac dysfunction during polymicrobial sepsis.
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DOI：
10.1097/ccm.0b013e3182535aeb
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发表时间：
2012-08
影响因子：
8.8
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Gao M;Ha T;Zhang X;Liu L;Wang X;Kelley J;Singh K;Kao R;Gao X;Williams D;Li C
To determine the role of Toll-like receptor 3 in cardiac dysfunction during polymicrobial sepsis. controlled animal study University Research Laboratory Male C57BL/6, Wild type, Toll-like receptor 3−/− 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 (WT, n=12) mice were subjected to CLP. Cardiac function was measured by echocardiography before and 6 hrs after CLP. 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 survive indefinitely, i.e. >200 hrs. TLR3 deficiency significantly decreased CLP-induced cardiac myocyte apoptosis and attenuated CLP-induced Fas and FasL expression in the myocardium. CLP-activation of TLR4-meidated NF-κB and TRIF-dependent IFN signaling pathways was prevented by TLR3 deficiency. In addition, CLP-increased VCAM-1 and ICAM-1 expression and neutrophil and macrophage sequestration in the myocardium were also attenuated in septic TLR3−/− mice. More significantly, adoptive transfer of WT bone marrow stromal cells to TLR3−/− mice abolished the cardioprotective effect in sepsis. These data indicate that TLR3 plays a deleterious role in mediating cardiac dysfunction in sepsis. Thus, modulation of TLR3 activity may be useful in preventing cardiac dysfunction in sepsis.
