Ventilator-induced Lung Injury Is Mediated by the NLRP3 Inflammasome
Ventilator-induced Lung Injury Is Mediated by the NLRP3 Inflammasome
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DOI：
10.1097/aln.0b013e3182518bc0
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发表时间：
2012-05-01
期刊：
影响因子：
8.8
通讯作者：
Wieland, Catharina W.
中科院分区：
文献类型：
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作者：
Kuipers, Maria T.;Aslami, Hamid;Wieland, Catharina W.
背景：先天免疫反应在呼吸机引起的肺损伤（VILI）中很重要，但所涉及的确切途径尚未阐明。作者研究了细胞内危险传感器 NLRP3 炎症小体的作用。方法：分析了从通气患者 (n = 40) 获得的呼吸道上皮细胞和肺泡巨噬细胞中的 NLRP3 炎症小体基因表达。此外，野生型和NLRP3炎性体缺陷小鼠被随机分配至低潮气量（约7.5 ml/kg）和高潮气量（约15 ml/kg）通气。研究了肺灌洗液中尿酸的存在、肺组织中 caspase-1 的激活和 NLRP3 炎性体基因的表达。此外，在开始机械通气之前，用白细胞介素-1受体拮抗剂、格列本脲或媒介物对小鼠进行预处理。 VILI终点是相对肺重量、灌洗液中的总蛋白、中性粒细胞流入以及肺和全身细胞因子和趋化因子浓度。数据代表平均值+/- SD。结果：机械通气上调肺泡巨噬细胞中NLRP3的信使RNA表达水平（1.0 +/- 0 vs. 1.70 +/- 1.65，P小于0.05）。在小鼠中，机械通气分别增加了 NLRP3 和凋亡相关斑点样蛋白信使 RNA 水平（1.08 +/- 0.55 与 3.98 +/- 2.89；P 小于 0.001 和 0.95 +/- 0.53 与 6.0 +/- 3.55；P 小于 0.001），激活 caspase-1，并增加尿酸水平（6.36 +/- 1.85 与 41.9 +/- 32.0，P 小于 0.001）。与野生型小鼠相比，NLRP3 炎性体缺陷小鼠由于高潮气量机械通气而表现出较少的 VILI。此外，使用白细胞介素1受体拮抗剂或格列本脲治疗可减少VILI。结论：机械通气诱导NLRP3炎症小体依赖性肺部炎症反应。 NLRP3 炎性体缺陷部分保护小鼠免受 VILI。
Background: The innate immune response is important in ventilator-induced lung injury (VILI) but the exact pathways involved are not elucidated. The authors studied the role of the intracellular danger sensor NLRP3 inflammasome.Methods: NLRP3 inflammasome gene expression was analyzed in respiratory epithelial cells and alveolar macrophages obtained from ventilated patients (n = 40). In addition, wild-type and NLRP3 inflammasome deficient mice were randomized to low tidal volume (approximately 7.5 ml/kg) and high tidal volume (approximately 15 ml/kg) ventilation. The presence of uric acid in lung lavage, activation of caspase-1, and NLRP3 inflammasome gene expression in lung tissue were investigated. Moreover, mice were pretreated with interleukin-1 receptor antagonist, glibenclamide, or vehicle before start of mechanical ventilation. VILI endpoints were relative lung weights, total protein in lavage fluid, neutrophil influx, and pulmonary and systemic cytokine and chemokine concentrations. Data represent mean +/- SD.Results: Mechanical ventilation up-regulated messenger RNA expression levels of NLRP3 in alveolar macrophages (1.0 +/- 0 vs. 1.70 +/- 1.65, P less than 0.05). In mice, mechanical ventilation increased both NLRP3 and apoptosis-associated speck-like protein messenger RNA levels, respectively (1.08 +/- 0.55 vs. 3.98 +/- 2.89; P less than 0.001 and 0.95 +/- 0.53 vs. 6.0 +/- 3.55; P less than 0.001), activated caspase-1, and increased uric acid levels (6.36 +/- 1.85 vs. 41.9 +/- 32.0, P less than 0.001). NLRP3 inflammasome deficient mice displayed less VILI due to high tidal volume mechanical ventilation compared with wild-type mice. Furthermore, treatment with interleukin-1 receptor antagonist or glibenclamide reduced VILI.Conclusions: Mechanical ventilation induced a NLRP3 inflammasome dependent pulmonary inflammatory response. NLRP3 inflammasome deficiency partially protected mice from VILI.