Department of Anesthesiology, Lung Vascular Biology Laboratory, University of Utah School of Medicine, Salt Lake City, UT 84132-2304, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 May 1;302(9):L816-28. doi: 10.1152/ajplung.00080.2011. Epub 2011 Dec 9.
Lung endothelial cells respond to changes in vascular pressure through mechanotransduction pathways that alter barrier function via non-Starling mechanism(s). Components of the endothelial glycocalyx have been shown to participate in mechanotransduction in vitro and in systemic vessels, but the glycocalyx's role in mechanosensing and pulmonary barrier function has not been characterized. Mechanotransduction pathways may represent novel targets for therapeutic intervention during states of elevated pulmonary pressure such as acute heart failure, fluid overload, and mechanical ventilation. Our objective was to assess the effects of increasing vascular pressure on whole lung filtration coefficient (K(fc)) and characterize the role of endothelial heparan sulfates in mediating mechanotransduction and associated increases in K(fc). Isolated perfused rat lung preparation was used to measure K(fc) in response to changes in vascular pressure in combination with superimposed changes in airway pressure. The roles of heparan sulfates, nitric oxide, and reactive oxygen species were investigated. Increases in capillary pressure altered K(fc) in a nonlinear relationship, suggesting non-Starling mechanism(s). nitro-l-arginine methyl ester and heparanase III attenuated the effects of increased capillary pressure on K(fc), demonstrating active mechanotransduction leading to barrier dysfunction. The nitric oxide (NO) donor S-nitrosoglutathione exacerbated pressure-mediated increase in K(fc). Ventilation strategies altered lung NO concentration and the K(fc) response to increases in vascular pressure. This is the first study to demonstrate a role for the glycocalyx in whole lung mechanotransduction and has important implications in understanding the regulation of vascular permeability in the context of vascular pressure, fluid status, and ventilation strategies.
肺血管内皮细胞通过改变屏障功能的非 Starling 机制（s）来响应血管压力的变化。已有研究表明，内皮糖萼的成分在体外和系统性血管中参与了力学转导，但糖萼在机械感应和肺屏障功能中的作用尚未得到描述。力学转导途径可能代表了在升高的肺压状态下（如急性心力衰竭、液体超负荷和机械通气）治疗干预的新靶点。我们的目的是评估血管压力升高对全肺滤过系数（Kfc）的影响，并描述内皮肝素硫酸盐在介导力学转导和相关的 Kfc 增加中的作用。我们使用离体灌注大鼠肺制备来测量血管压力变化时的 Kfc，并结合气道压力的叠加变化。研究了肝素硫酸盐、一氧化氮和活性氧的作用。毛细血管压力的增加以非线性关系改变了 Kfc，表明存在非 Starling 机制（s）。硝基-l-精氨酸甲酯和肝素酶 III 减弱了毛细血管压力对 Kfc 的影响，表明存在主动力学转导导致屏障功能障碍。一氧化氮（NO）供体 S-亚硝基谷胱甘肽加剧了压力介导的 Kfc 增加。通气策略改变了肺 NO 浓度和血管压力升高时 Kfc 的反应。这是第一项证明糖萼在全肺力学转导中起作用的研究，对于理解血管通透性在血管压力、液体状态和通气策略背景下的调节具有重要意义。
