Department of Surgery, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Alcohol Clin Exp Res. 2010 Oct;34(10):1733-41. doi: 10.1111/j.1530-0277.2010.01260.x. Epub 2010 Jul 1.
Clinical and laboratory evidence suggests that alcohol consumption prior to burn injury leads to dysregulated immune function and subsequent higher rates of morbidity and mortality. Our laboratory previously observed higher levels of pro-inflammatory cytokines and leukocyte infiltration in the lungs of mice following ethanol and burn injury. To understand the mechanism of the increased inflammatory response, we looked at different signaling initiators of inflammation including toll-like receptors 2 and 4 (TLR2 and 4) pathways.
Wild-type, TLR2, and TLR4 knockout mice were treated with vehicle or a single binge dose of ethanol (1.11 g/kg) and subsequently given a sham or burn injury. Twenty-four hours postinjury, systemic and pulmonary levels of pro-inflammatory cytokines were quantified, and differences in neutrophil infiltration were determined by histological examination.
Higher numbers of neutrophils were observed in the lungs of wild-type mice following the combined insult of ethanol and burn injury relative to either injury alone. This increase in leukocyte accumulation was absent in the TLR4 knockout mice. Circulating levels of IL-6 and tumor necrosis factor-α were also elevated in wild-type mice but not in TLR4 knockout mice. Consistent with these findings, pulmonary levels of KC and IL-6 were increased in wild-type mice following burn and ethanol compared to burn injury alone as well as to their TLR4 knockout counterparts. In contrast, TLR2 knockout mice displayed similar levels, to wild-type mice, of neutrophil infiltration as well as IL-6 and KC in the lung.
These data suggest that TLR4 signaling is a crucial contributory component in the exuberant inflammation after ethanol and burn injury. However, TLR2 does not appear to play a vital role in the aberrant pulmonary inflammation.
临床和实验室证据表明，烧伤前饮酒会导致免疫功能失调，随后发病率和死亡率更高。我们的实验室之前观察到，乙醇和烧伤后小鼠肺部的促炎细胞因子和白细胞浸润水平更高。为了了解炎症反应增强的机制，我们研究了不同的炎症信号起始子，包括 Toll 样受体 2 和 4（TLR2 和 4）途径。
野生型、TLR2 和 TLR4 基因敲除小鼠用载体或单次 binge 剂量的乙醇（1.11 g/kg）处理，然后给予假手术或烧伤损伤。损伤后 24 小时，定量检测全身和肺部促炎细胞因子水平，并通过组织学检查确定中性粒细胞浸润的差异。
与单独损伤相比，乙醇和烧伤联合损伤后，野生型小鼠肺部观察到更多的中性粒细胞。TLR4 基因敲除小鼠中白细胞积聚增加的情况不存在。循环中 IL-6 和肿瘤坏死因子-α 的水平也在野生型小鼠中升高，但在 TLR4 基因敲除小鼠中没有升高。与这些发现一致的是，与单独烧伤相比，烧伤和乙醇后，野生型小鼠的肺 KC 和 IL-6 水平升高，与 TLR4 基因敲除小鼠相比也是如此。相比之下，TLR2 基因敲除小鼠的中性粒细胞浸润以及肺中 IL-6 和 KC 的水平与野生型小鼠相似。
这些数据表明，TLR4 信号是乙醇和烧伤后过度炎症的关键贡献成分。然而，TLR2 在异常的肺炎症中似乎没有发挥重要作用。
