Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice
Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice
复制标题
DOI：
10.1161/01.cir.0000112575.66565.84
复制
发表时间：
2004-02-17
期刊：
影响因子：
37.8
通讯作者：
Bourcier, T
中科院分区：
文献类型：
--
作者：
Oyama, J;Blais, C;Bourcier, T
背景-心肌缺血和再灌注诱导的组织损伤涉及强烈的炎症反应，但再灌注损伤的近端事件仍不完全确定。Toll样受体4（TLR 4）是革兰氏阴性病原体对脂多糖的天然免疫应答中的近端信号受体。TLR 4也在心脏和脉管系统中表达，但TLR 4在心肌对与微生物病原体分离的损伤的反应中的作用尚未被研究。本研究评估了TLR 4在缺血-再灌注损伤的小鼠模型中心肌梗死和炎症中的作用。方法和结果-在2种TLR 4缺陷小鼠（C57/BL 10 ScCr和C3 H/HeJ）和对照（C57/BL 10 ScSn和C3 H/OuJ）上进行心肌缺血-再灌注（MIR）。对小鼠进行1小时的冠状动脉结扎，随后进行24小时的再灌注。TLR 4缺陷小鼠与对照组小鼠相比，具有类似风险区域的小鼠持续的梗死明显较小。MIR后TLR 4缺陷型Cr小鼠的心肌浸润的中性粒细胞较少，表现为髓过氧化物酶活性较低和CD 45/GR 1阳性细胞较少。TLR 4-缺陷型Cr小鼠的心肌含有较少的脂质过氧化物和较少的补体沉积与对照小鼠相比，MIR后。血清白细胞介素-12，干扰素-γ和内毒素水平在缺血再灌注后没有增加。在腹膜中的神经元贩运是相似的，在所有菌株注射后的巯基乙酸盐。结论-TLR 4缺陷小鼠心肌缺血再灌注损伤后，维持较小的梗死和炎症反应较少。这些数据表明，除了其在先天性免疫反应中的作用，TLR 4在小鼠心肌缺血-再灌注损伤中起促炎作用。
Background - Myocardial ischemia and reperfusion- induced tissue injury involve a robust inflammatory response, but the proximal events in reperfusion injury remain incompletely defined. Toll-like receptor 4 (TLR4) is a proximal signaling receptor in innate immune responses to lipopolysaccharide of Gram-negative pathogens. TLR4 is also expressed in the heart and vasculature, but a role for TLR4 in the myocardial response to injury separate from microbial pathogens has not been examined. This study assessed the role of TLR4 in myocardial infarction and inflammation in a murine model of ischemia-reperfusion injury.Methods and Results - Myocardial ischemia-reperfusion (MIR) was performed on 2 strains of TLR4-deficient mice (C57/BL10 ScCr and C3H/HeJ) and controls (C57/BL10 ScSn and C3H/OuJ). Mice were subjected to 1 hour of coronary ligation, followed by 24 hours of reperfusion. TLR4-deficient mice sustained significantly smaller infarctions compared with control mice given similar areas at risk. Fewer neutrophils infiltrated the myocardium of TLR4-deficient Cr mice after MIR, indicated by less myeloperoxidase activity and fewer CD45/GR1-positive cells. The myocardium of TLR4-deficient Cr mice contained fewer lipid peroxides and less complement deposition compared with control mice after MIR. Serum levels of interleukin-12, interferon-gamma, and endotoxin were not increased after ischemia-reperfusion. Neutrophil trafficking in the peritoneum was similar in all strains after injection of thioglycollate.Conclusions - TLR4-deficient mice sustain smaller infarctions and exhibit less inflammation after myocardial ischemia-reperfusion injury. The data suggest that in addition to its role in innate immune responses, TLR4 serves a proinflammatory role in murine myocardial ischemia-reperfusion injury.