Department of Surgery, Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
Crit Care Med. 2012 Aug;40(8):2390-9. doi: 10.1097/CCM.0b013e3182535aeb.
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 (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 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-κB and Toll/IL-1 receptor-domain-containing adapter-inducing interferon-β-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.
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.
确定 Toll 样受体 3 在多微生物脓毒症中心脏功能障碍中的作用。
对照动物研究。
大学研究实验室。
雄性 C57BL/6、野生型、Toll 样受体 3-/-。
心肌功能障碍是感染性休克的主要后果，并导致脓毒症的高死亡率。Toll 样受体 (TLR) 在脓毒症/感染性休克的病理生理学中发挥着关键作用。TLR3 位于细胞内内体中，并识别双链 RNA。本研究探讨了 TLR3 在盲肠结扎和穿刺 (CLP) 诱导的脓毒症后心脏功能障碍中的作用。TLR3 敲除 (TLR3-/-，n=12) 和年龄匹配的野生型 (n=12) 小鼠接受 CLP。CLP 前后通过超声心动图测量心功能。
CLP 导致心脏功能显著障碍，射血分数分别降低 25.7%，缩短分数降低 29.8%。然而，TLR3-/- 小鼠的心脏功能保持在 CLP 前水平。野生型小鼠在 CLP 后 58 小时有 50%的死亡率，在 154 小时有 100%的死亡率。相比之下，70%的 TLR3-/- 小鼠存活超过 200 小时。TLR3 缺乏显著降低 CLP 诱导的心肌细胞凋亡，并减轻 CLP 诱导的心肌 Fas 和 Fas 配体表达。TLR3 缺乏可防止 CLP 激活 TLR4 介导的核因子-κB 和 Toll/IL-1 受体结构域包含衔接诱导干扰素-β依赖的干扰素信号通路。此外，CLP 增加的血管细胞粘附分子-1 和细胞间粘附分子-1 表达，以及中性粒细胞和巨噬细胞在心肌中的隔离也在脓毒症 TLR3-/- 小鼠中减弱。更重要的是，将野生型骨髓基质细胞过继转移至 TLR3-/- 小鼠可消除脓毒症中的心脏保护作用。
这些数据表明，TLR3 在介导脓毒症中心脏功能障碍方面起着有害作用。因此，调节 TLR3 活性可能有助于预防脓毒症中的心脏功能障碍。
