ALTERATIONS IN THE CARDIAC INFLAMMATORY RESPONSE TO BURN TRAUMA IN MICE LACKING A FUNCTIONAL TOLL-LIKE RECEPTOR 4 GENE
ALTERATIONS IN THE CARDIAC INFLAMMATORY RESPONSE TO BURN TRAUMA IN MICE LACKING A FUNCTIONAL TOLL-LIKE RECEPTOR 4 GENE
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DOI：
10.1097/shk.0b013e318173f329
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发表时间：
2008-12-01
期刊：
影响因子：
3.1
通讯作者：
Carlson, Deborah
中科院分区：
文献类型：
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作者：
Bruns, Brandon;Maass, David;Carlson, Deborah
我们的团队和其他人之前已经证明，Toll样受体4(TLR-4)的失活可以预防烧伤所致的心肌收缩功能障碍；然而，参与这种心脏保护的分子机制还没有很好地确定。本研究探讨TLR-4在心脏热损伤炎症反应中的作用。C3H/HeJ(TLR-4突变小鼠)和C3H/HEN野生型(WT)小鼠造成假烧伤或40%Ⅲ度烧伤，按Parkland公式用乳酸林格液复苏。分别于假手术或烧伤后2、4、24 h处死小鼠，每组7~9只，取心脏组织。免疫印迹法检测磷酸化p38丝裂原活化蛋白激酶(MAPK)、胞核p50和胞浆p50。核因子-kappa B也通过凝胶迁移率改变分析进行了鉴定。采用酶联免疫吸附试验检测全身和心肌细胞分泌的肿瘤坏死因子-α、白介素1β、白介素6和白介素10。WT小鼠烧伤可促进心肌炎症信号，包括磷酸化p38MAPK、核p50的表达增加，以及心肌细胞分泌细胞因子的增加。WT动物的全身细胞因子也增加了，尽管没有达到心肌细胞因子表达的程度。Toll样受体4失活导致烧伤诱导的几种反应减弱，包括p38MAPK的磷酸化，核因子-kappa B的核转位和细胞因子的分泌。这些数据表明，烧伤通过Toll/IL-1信号在心脏启动炎症反应，从而导致心脏损伤和收缩功能障碍。
Our group and others have previously shown that Toll-like receptor 4 (TLR-4) inactivation prevents burn-induced myocardial contractile dysfunction; however, the molecular mechanisms that are involved in this cardioprotection are not well defined. This present study examines the involvement of TLR-4 in the cardiac inflammatory response to thermal insult. C3H/HeJ (TLR-4 mutant mice) and C3H/HeN wild-type (WT) mice were subjected to either a sham burn or 40% full-thickness burn injury and were fluid resuscitated with lactated Ringer using the Parkland formula. Mice (n = 7-9 per group) were killed at 2, 4, or 24 h postsham or burn, and heart tissue was harvested. Immunoblotting was performed to evaluate phosphorylated p38 mitogen-activated protein kinase (MAPK), nuclear p50, and cytoplasmic p50. Nuclear factor-kappa B was also characterized via electrophoretic mobility shift assay. Systemic and cardiac myocyte secretion of TNF-alpha, IL-1 beta, IL-6, and IL-10 were measured by enzyme-linked immunosorbent assay. Burn injury in WT mice promoted myocardial inflammatory signaling that included increased expression of phosphorylated p38 MAPK, nuclear p50, and increased cardiac myocyte secretion of cytokines. Systemic cytokines were also increased in WT animals, although not to the extent of the myocardial cytokine expression. Toll-like receptor 4 inactivation resulted in an attenuation of several burn-induced responses, including phosphorylation of p38 MAPK, nuclear translocation of nuclear factor-kappa B, and cytokine secretion. These data suggest that burn injury initiates an inflammatory response via Toll/IL-1 signaling in the heart, which contributes to cardiac injury and contractile dysfunction.