Oyama Jun-ichi, Blais Charles, Liu Xiaoli, Pu Minying, Kobzik Lester, Kelly Ralph A, Bourcier Todd
Department of Cardiovascular Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Boston, Mass 02115, USA.
Circulation. 2004 Feb 17;109(6):784-9. doi: 10.1161/01.CIR.0000112575.66565.84.
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.
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.
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.
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未完全明确。Toll样受体4（TLR4）是对革兰氏阴性病原体脂多糖的天然免疫反应中的近端信号受体。TLR4也在心脏和血管系统中表达，但TLR4在心肌对损伤的反应中独立于微生物病原体的作用尚未得到研究。本研究评估了TLR4在缺血再灌注损伤小鼠模型中对心肌梗死和炎症的作用。
对2种TLR4缺陷小鼠品系（C57/BL10 ScCr和C3H/HeJ）及对照品系（C57/BL10 ScSn和C3H/OuJ）进行心肌缺血再灌注（MIR）。小鼠接受1小时冠状动脉结扎，随后进行24小时再灌注。与具有相似危险区域的对照小鼠相比，TLR4缺陷小鼠的梗死面积明显更小。MIR后，TLR4缺陷的Cr小鼠心肌中浸润的中性粒细胞较少，髓过氧化物酶活性较低以及CD45/GR1阳性细胞较少表明了这一点。与MIR后的对照小鼠相比，TLR4缺陷的Cr小鼠心肌中的脂质过氧化物较少且补体沉积较少。缺血再灌注后，血清白细胞介素-12、干扰素-γ和内毒素水平未升高。注射巯基乙酸盐后，所有品系小鼠腹膜中的中性粒细胞迁移情况相似。
TLR4缺陷小鼠在心肌缺血再灌注损伤后梗死面积较小且炎症反应较轻。数据表明，TLR4除了在天然免疫反应中发挥作用外，在小鼠心肌缺血再灌注损伤中还起促炎作用。
