Carbon monoxide protects against ventilator-induced lung injury via PPAR-γ and inhibition of Egr-1
Carbon monoxide protects against ventilator-induced lung injury via PPAR-γ and inhibition of Egr-1
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DOI：
10.1164/rccm.200708-1265oc
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发表时间：
2008-06-01
影响因子：
24.7
通讯作者：
Choi, Augustine M. K.
中科院分区：
文献类型：
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作者：
Hoetzel, Alexander;Dolinay, Tamas;Choi, Augustine M. K.
呼吸机诱导的肺损伤（VILI）导致不可接受的高死亡率。在这方面，吸入一氧化碳（CO）的呼吸特性可以提供一个治疗的选择。Objectives：本研究探讨了CO依赖的保护机制在小鼠模型VILI.Methods：小鼠通气（12 ml/kg，1-8 h）与空气中存在或不存在的CO（250 ppm）。监测气道压力、血压和血气。分析肺组织的炎症、损伤和基因表达。支气管肺泡灌洗液中的蛋白质，细胞和中性粒细胞计数，和cytokines.Measurements和主要结果：机械通气引起显着的肺损伤，反映在支气管肺泡灌洗液中的蛋白质浓度，总细胞和中性粒细胞计数的增加，以及血红素氧合酶-1和热休克蛋白-70在肺组织中的诱导。与此相反，CO的应用，防止肺损伤，在通气，抑制应激基因上调，减少肺中性粒细胞浸润。这些作用之前的抑制通气诱导的细胞因子和趋化因子的生产。此外，CO阻止早期通气依赖性的早期生长反应-1（Egr-1）的上调。相对于野生型小鼠，Egr-1缺陷型小鼠在通气后没有持续肺损伤，这表明Egr-1在VILI中作为关键的促炎调节剂。此外，抑制过氧化物酶体增殖物激活受体（PPAR）-γ，一个神经元的核调节，由GW 9662废除了CO的保护作用。结论：机械通气造成深刻的肺损伤和炎症反应。CO处理在该模型中赋予依赖于PPAR-gamma和Egr-1抑制的保护作用。
Rationale Ventilator-induced lung injury (VILI) leads to an unacceptably high mortality. In this regard, the antiinflammatory properties of inhaled carbon monoxide (CO) may provide a therapeutic option.Objectives: This study explores the mechanisms of CO-dependent protection in a mouse model of VILI.Methods: Mice were ventilated (12 ml/kg, 1-8 h) with air in the absence or presence of CO (250 ppm). Airway pressures, blood pressure, and blood gases were monitored. Lung tissue was analyzed for inflammation, injury, and gene expression. Bronchoalveolar lavage fluid was analyzed for protein, cell and neutrophil counts, and cytokines.Measurements and Main Results: Mechanical ventilation caused significant lung injury reflected by increases in protein concentration, total cell and neutrophil counts in the bronchoalveolar lavage fluid, as well as the induction of heme oxygenase-1 and heat shock protein-70 in lung tissue. In contrast, CO application prevented lung injury during ventilation, inhibited stress-gene up-regulation, and decreased lung neutrophil infiltration. These effects were preceded by the inhibition of ventilation-induced cytokine and chemokine production. Furthermore, CO prevented the early ventilation-dependent up-regulation of early growth response-1 (Egr-1). Egr-1-deficient mice did not sustain lung injury after ventilation, relative to wild-type mice, suggesting that Egr-1 acts as a key proinflammatory regulator in VILI. Moreover, inhibition of peroxysome proliferator-activated receptor (PPAR)-gamma, an antiinflammatory nuclear regulator, by GW9662 abolished the protective effects of CO.Conclusions: Mechanical ventilation causes profound lung injury and inflammatory responses. CO treatment conferred protection in this model dependent on PPAR-gamma and inhibition of Egr-1.