Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation.
Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation.
复制标题
Toll样受体4介导内毒素和过度充气诱导的中性粒细胞固次和肺损伤。
DOI：
10.1097/ccm.0b013e3181bc7c17
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发表时间：
2010-01
影响因子：
8.8
通讯作者：
Minshall RD
中科院分区：
文献类型：
--
作者：
Hu G;Malik AB;Minshall RD
多形核中性粒细胞浸润入肺是呼吸机诱导的肺炎相关肺损伤的一个重要特征，但中性粒细胞募集的机制尚不清楚。使用Toll样受体4基因敲除（tl 4 r −/−）小鼠，我们探讨了Toll样受体4信号转导在介导中性粒细胞募集和脂多糖激发结合肺过度充气诱导的肺损伤中的作用。实验动物模型。大学实验室。tlr 4 −/−和野生型C57 BL/6小鼠。通过气管内滴注脂多糖（0.3 mg/kg）2 h激发野生型或tlr 4 −/−小鼠，然后再进行正常（7 ml/kg）或高潮气量（28 ml/kg）通气2 h。在其他研究中，将野生型或tlr 4 −/−小鼠的中性粒细胞用脂多糖预处理30分钟，然后输注到离体肺制备物中30分钟，同时以25 cmH 2 O峰值吸气压对肺通气。与暴露于正常潮气量通气的未激发小鼠相比，以28 ml/kg潮气量通气的脂多糖激发野生型小鼠表现出中性粒细胞隔离增加12倍，支气管肺泡灌洗液中性粒细胞计数增加18倍，支气管肺泡灌洗液白蛋白浓度增加6倍，肺含水量增加1.6倍。然而，tlr 4 −/−小鼠表现出可忽略的中性粒细胞隔离、微血管屏障破坏或水肿形成。单独机械通气或与脂多糖联合使用可导致野生型小鼠循环中性粒细胞和肺内皮细胞活化，而这在tlr 4 −/−小鼠中被阻止。肺炎/脓毒症期间的大潮气量通气通过Toll样受体4依赖性信号通路诱导肺中性粒细胞隔离和损伤结果表明，Toll样受体4在肺中性粒细胞隔离和急性肺损伤的机制中起重要作用，当肺炎/脓毒症与肺过度充气相耦合时。
Infiltration of polymorphonuclear neutrophils into the lung is an important feature of ventilator-induced lung injury associated with pneumonia, but the mechanisms involved in neutrophil recruitment are poorly understood. Using Toll-like receptor 4 knockout (tl4r−/−) mice, we addressed the role of Toll-like receptor 4 signaling in mediating neutrophil recruitment and lung injury induced by lipopolysaccharide challenge coupled to lung hyperinflation. Experimental animal model. University laboratory. tlr4−/− and wild-type C57BL/6 mice. Wild type or tlr4−/− mice were challenged by intratracheal instillation of lipopolysaccharide (0.3 mg/kg) for 2 h and then subjected to normal (7 ml/kg) or high (28 ml/kg) tidal volume ventilation for another 2 h. In other studies, neutrophils from wild type or tlr4−/− mice were pretreated with lipopolysaccharide for 30 min and then infused into the isolated lung preparation for 30 min while the lungs were ventilated with 25 cmH2O peak inspiratory pressure. Lipopolysaccharide-challenged wild type mice ventilated with a 28 ml/kg tidal volume exhibited 12-fold increase in neutrophil sequestration, 18-fold increase in bronchoalveolar lavage neutrophil count, 6-fold increase in bronchoalveolar lavage albumin concentration, and 1.6-fold increase in lung water content compared to unchallenged mice exposed to normal tidal volume ventilation. However, tlr4−/− mice showed negligible neutrophil sequestration, microvascular barrier breakdown, or edema formation. Mechanical ventilation alone or combined with lipopolysaccharide caused activation of circulating neutrophils and pulmonary endothelium in wild type mice whereas this was prevented in tlr4−/− mice. High tidal volume ventilation during pneumonia/sepsis induces lung neutrophil sequestration and injury via the Toll-like receptor 4-dependent signaling pathway. The results suggest an important role of Toll-like receptor 4 in the mechanism of lung neutrophil sequestration and acute lung injury when pneumonia/sepsis is coupled to lung hyperinflation.