Role of caveolin-1 expression in the pathogenesis of pulmonary edema in ventilator-induced lung injury.
Role of caveolin-1 expression in the pathogenesis of pulmonary edema in ventilator-induced lung injury.
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DOI：
10.4103/2045-8932.105033
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发表时间：
2012-10
影响因子：
2.6
通讯作者：
Minshall RD
中科院分区：
文献类型：
--
作者：
Maniatis NA;Kardara M;Hecimovich D;Letsiou E;Castellon M;Roussos C;Shinin V;Votta-Vellis EG;Schwartz DE;Minshall RD
Caveolin-1是肺内皮屏障功能的关键调节因子。在这里，我们测试的假设，小窝蛋白-1的表达所需的呼吸机诱导的肺损伤（VILI）。Caveolin-1基因破坏（Cav-1-/-）和年龄、性别和品系匹配的野生型（WT）对照小鼠使用两种方案进行通气：保护性（8 mL/kg）体积控制和损伤性（8 mL/kg）体积控制。（21 mL/Kg）潮气量，持续6小时;并采用压力控制的保护性通气（气道压力= 12 cm H2O）与损伤性通气（30 cm H2O）诱导肺损伤。测量肺微血管通透性（全肺125 I-白蛋白蓄积、肺毛细血管滤过系数[Kf，c]）和炎症标志物（支气管肺泡灌洗[BAL]细胞因子水平和中性粒细胞计数）。我们还评估了肺组织切片，以及Src激酶激活和小窝蛋白-1磷酸化的时间过程。VILI诱导肺125 I-白蛋白蓄积增加1.7倍，Kf，c增加4倍，细胞因子CXCL 1和白细胞介素-6水平显著增加，并促进WT小鼠BAL嗜中性粒细胞增多。这些标准的肺损伤在Cav-1-/-小鼠中显著减少，但通过静脉注射脂质体/Cav-1 cDNA复合物完全恢复，该复合物拯救了肺微血管中Cav-1的表达。由于已知凝血酶在介导牵张诱导的血管损伤中起重要作用，我们在培养的小鼠肺微血管内皮细胞（MLEC）中观察到凝血酶诱导的白蛋白通透性过高和WT中p44/42 MAP激酶的磷酸化，但在Cav-1-/-MLEC中没有。因此，小窝蛋白-1的表达是所需的机械拉伸诱导的肺部炎症和内皮细胞通透性过高，在体外和体内。
Caveolin-1 is a key regulator of pulmonary endothelial barrier function. Here, we tested the hypothesis that caveolin-1 expression is required for ventilator-induced lung injury (VILI). Caveolin-1 gene-disrupted (Cav-1-/-) and age-, sex-, and strain-matched wild-type (WT) control mice were ventilated using two protocols: volume-controlled with protective (8 mL/kg) versus injurious (21 mL/Kg) tidal volume for up to 6 hours; and pressure-controlled with protective (airway pressure = 12 cm H2O) versus injurious (30 cm H2O) ventilation to induce lung injury. Lung microvascular permeability (whole-lung 125I-albumin accumulation, lung capillary filtration coefficient [Kf, c]) and inflammatory markers (bronchoalveolar lavage [BAL] cytokine levels and neutrophil counts) were measured. We also evaluated histologic sections from lungs, and the time course of Src kinase activation and caveolin-1 phosphorylation. VILI induced a 1.7-fold increase in lung 125I-albumin accumulation, fourfold increase in Kf, c, significantly increased levels of cytokines CXCL1 and interleukin-6, and promoted BAL neutrophilia in WT mice. Lung injury by these criteria was significantly reduced in Cav-1-/- mice but fully restored by i.v. injection of liposome/Cav-1 cDNA complexes that rescued expression of Cav-1 in lung microvessels. As thrombin is known to play a significant role in mediating stretch-induced vascular injury, we observed in cultured mouse lung microvascular endothelial cells (MLECs) thrombin-induced albumin hyperpermeability and phosphorylation of p44/42 MAP kinase in WT but not in Cav-1-/- MLECs. Thus, caveolin-1 expression is required for mechanical stretch-induced lung inflammation and endothelial hyperpermeability in vitro and in vivo.