Atrial natriuretic peptide attenuates LPS-induced lung vascular leak: role of PAK1
Atrial natriuretic peptide attenuates LPS-induced lung vascular leak: role of PAK1
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DOI：
10.1152/ajplung.00202.2009
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发表时间：
2010-11-01
影响因子：
4.9
通讯作者：
Birukov, Konstantin G.
中科院分区：
文献类型：
--
作者：
Birukova, Anna A.;Xing, Junjie;Birukov, Konstantin G.
毕鲁科娃AA，邢杰，傅平，雅库博夫B， Dubrovskyi O, Fortune JA, Klibanov AM，比鲁科夫KG。房利钠肽减轻lps诱导的肺血管渗漏：PAK1的作用。[J] .中国生物医学工程学报，2015,31(2):559 - 563。首次发表于2010年8月20日；doi: 10.1152 / ajplung.00202.2009。在脓毒症、肺水肿和急性呼吸窘迫综合征（ARDS）模型中，心房利钠肽（ANP）水平升高提示其在急性肺损伤调节中的潜在作用。我们最近描述了anp对凝血酶诱导的肺内皮细胞（EC）屏障功能障碍的保护作用。本研究在细菌壁LPS诱导的肺血管通透性模型中，检测了Rac效应物p21活化激酶（PAK1）参与anp保护作用。C57BL/6J小鼠或ANP基因敲除小鼠（Nppa(-/-)）分别用LPS（气管内0.63 mg/kg）加或不加ANP （2 μ g/kg iv）处理。通过测量支气管肺泡灌洗液蛋白含量、细胞计数、埃文斯蓝外渗和肺组织学来监测肺损伤。通过形态学分析和跨内皮电阻测量来评估内皮屏障特性。ANP刺激rac依赖性PAK1磷酸化，减弱LPS、tnf - α和IL-6引起的内皮通透性，减少LPS诱导的支气管肺泡灌洗液中细胞和蛋白的积累，抑制急性肺损伤小鼠模型的Evans蓝色外渗。ANP敲除小鼠lps诱导的肺损伤和血管渗漏更为严重。在救援实验中，ANP注射液可显著减轻LPS引起的Nppa（-/-）小鼠肺损伤。PAK1的分子抑制抑制了ANP治疗对lps诱导的肺损伤和内皮屏障功能障碍的保护作用。本研究表明，ANP对lps诱导的血管泄漏的保护作用至少部分是由pak1依赖性信号通路介导的，导致EC屏障增强。我们的数据表明，ANP通过调节小GTPase信号在内皮屏障调节中起直接作用。
Birukova AA, Xing J, Fu P, Yakubov B, Dubrovskyi O, Fortune JA, Klibanov AM, Birukov KG. Atrial natriuretic peptide attenuates LPS-induced lung vascular leak: role of PAK1. Am J Physiol Lung Cell Mol Physiol 299: L652-L663, 2010. First published August 20, 2010; doi:10.1152/ajplung.00202.2009.-Increased levels of atrial natriuretic peptide (ANP) in the models of sepsis, pulmonary edema, and acute respiratory distress syndrome (ARDS) suggest its potential role in the modulation of acute lung injury. We have recently described ANP-protective effects against thrombin-induced barrier dysfunction in pulmonary endothelial cells (EC). The current study examined involvement of the Rac effector p21-activated kinase (PAK1) in ANP-protective effects in the model of lung vascular permeability induced by bacterial wall LPS. C57BL/6J mice or ANP knockout mice (Nppa(-/-)) were treated with LPS (0.63 mg/kg intratracheal) with or without ANP (2 mu g/kg iv). Lung injury was monitored by measurements of bronchoalveolar lavage protein content, cell count, Evans blue extravasation, and lung histology. Endothelial barrier properties were assessed by morphological analysis and measurements of transendothelial electrical resistance. ANP treatment stimulated Rac-dependent PAK1 phosphorylation, attenuated endothelial permeability caused by LPS, TNF-alpha, and IL-6, decreased LPS-induced cell and protein accumulation in bronchoalveolar lavage fluid, and suppressed Evans blue extravasation in the murine model of acute lung injury. More severe LPS-induced lung injury and vascular leak were observed in ANP knockout mice. In rescue experiments, ANP injection significantly reduced lung injury in Nppa(-/-) mice caused by LPS. Molecular inhibition of PAK1 suppressed the protective effects of ANP treatment against LPS-induced lung injury and endothelial barrier dysfunction. This study shows that the protective effects of ANP against LPS-induced vascular leak are mediated at least in part by PAK1-dependent signaling leading to EC barrier enhancement. Our data suggest a direct role for ANP in endothelial barrier regulation via modulation of small GTPase signaling.