Uhlig Stefan, Yang Yang, Waade Josephine, Wittenberg Claudia, Babendreyer Aaron, Kuebler Wolfgang M
Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany.
Cell Physiol Biochem. 2014;34(1):1-19. doi: 10.1159/000362980. Epub 2014 Jun 16.
In the lungs, increased vascular permeability can lead to acute lung injury. Because vascular permeability is regulated primarily by endothelial cells, many researchers have studied endothelial cell monolayers in culture, in order to understand the pathomechanisms of pulmonary edema. Such studies are based on the assumption that endothelial cells in culture behave like endothelial cells in situ. Here we show that this assumption is largely unfounded. Cultured endothelial cells show profound differences compared to their physiological counterparts, including a dysregulated calcium homeostasis. They fail to reproduce the pulmonary responses to agents such as platelet-activating factor. In contrast, they respond in a Rho-kinase depend fashion to thrombin, LPS or TNF. This is a striking finding for three reasons: (i) in the lungs, none of these agents increases vascular permeability by a direct interaction with endothelial cells; (ii) The endothelial Rho-kinase pathway seems to play little role in the development of pulmonary edema; (iii) This response pattern is similar for many endothelial cells in culture irrespective of their origin, which is in contrast to the stark heterogeneity of endothelial cells in situ. It appears that most endothelial in culture tend to develop a similar phenotyp that is not representative of any of the known endothelial cells of the lungs. We conclude that at present cultured endothelial cells are not useful to study the pathomechanisms of pulmonary edema.
在肺部，血管通透性增加可导致急性肺损伤。由于血管通透性主要由内皮细胞调节，许多研究人员对培养中的内皮细胞单层进行了研究，以了解肺水肿的发病机制。此类研究基于这样一种假设，即培养中的内皮细胞与原位内皮细胞表现相似。在此我们表明，这一假设在很大程度上是没有根据的。与生理状态下的内皮细胞相比，培养的内皮细胞表现出显著差异，包括钙稳态失调。它们无法重现肺部对诸如血小板活化因子等物质的反应。相反，它们以一种依赖Rho激酶的方式对凝血酶、脂多糖或肿瘤坏死因子作出反应。这一发现之所以引人注目，有三个原因：（i）在肺部，这些物质中没有一种通过与内皮细胞的直接相互作用来增加血管通透性；（ii）内皮Rho激酶途径似乎在肺水肿的发生发展中作用不大；（iii）培养中的许多内皮细胞，无论其来源如何，这种反应模式都是相似的，这与原位内皮细胞的明显异质性形成对比。似乎培养中的大多数内皮细胞倾向于形成一种相似的表型，这种表型并不代表肺部任何一种已知的内皮细胞。我们得出结论，目前培养的内皮细胞对于研究肺水肿的发病机制并无用处。
