Rottlerin causes pulmonary edema in vivo:: a possible role for PKCδ
Rottlerin causes pulmonary edema in vivo:: a possible role for PKCδ
复制标题
DOI：
10.1152/japplphysiol.00695.2007
复制
发表时间：
2007-12-01
影响因子：
3.3
通讯作者：
Harrington, Elizabeth O.
中科院分区：
文献类型：
--
作者：
Klinger, James R.;Murray, Josh D.;Harrington, Elizabeth O.
Rottlerin在体内引起肺水肿：PKC δ的可能作用。J Appl Physiol 103：2084-2094，2007.首次发表于2007年9月27日; doi：10.1152/japplphysiol.00695.2007。在本研究中，我们评估了在体外和体内对蛋白激酶C（PKC）亚型具有选择性的化学抑制剂对肺屏障功能的影响。Rottlerin是一种PKC δ抑制剂，但不是其他化学抑制剂，在体外剂量依赖性地促进肺内皮细胞屏障功能障碍。这种屏障功能障碍与局灶性粘连和应力纤维的结构变化相关，这与细胞硬度的功能变化一致。为了确定体外观察到的效应是否与完整肺的变化相关，我们使用离体和体内模型测试了罗特勒林在大鼠肺水肿形成中的作用。与溶剂处理的肺相比，分离的灌注肺在暴露于罗特勒林时表现出过滤系数的显著增加，这种作用与伊文思蓝染料（EBD）结合的白蛋白的外渗增加相关。此外，与溶剂相比，动物暴露于罗特勒素后，湿肺重量与干肺重量的比值显著更大;罗特勒素还导致EBD外渗至肺中的剂量依赖性增加。这些对肺水肿的影响发生时，右心室压力没有任何增加。对离体肺水肿的显微镜评估表明，在罗特勒林暴露的肺中，血管周围形成袖套，无间隔毛细血管渗漏的证据。两者合计，rottlerin增加肺内皮细胞单层的屏障功能障碍，并导致大鼠肺水肿;结果提示PKC δ在维持肺内皮屏障功能中的重要作用。
Rottlerin causes pulmonary edema in vivo: a possible role for PKC delta. J Appl Physiol 103: 2084-2094, 2007. First published September 27, 2007; doi: 10.1152/japplphysiol.00695.2007.-In the present study, we assessed the effects of chemical inhibitors shown to be selective for protein kinase C (PKC) isoforms on lung barrier function both in vitro and in vivo. Rottlerin, a purported inhibitor of PKC delta, but not other chemical inhibitors, dose dependently promoted barrier dysfunction in lung endothelial cells in vitro. This barrier dysfunction correlated with structural changes in focal adhesions and stress fibers, which were consistent with functional changes in cell stiffness. To determine whether the effects noted in vitro correlated with changes in intact lungs, we tested the effects of rottlerin in the formation of pulmonary edema in rats using both ex vivo and in vivo models. Isolated, perfused lungs demonstrated a significant increase in filtration coefficients on exposure to rottlerin, compared with vehicle-treated lungs, an effect that correlated with increased extravasation of Evan's blue dye (EBD)-conjugated albumin. Additionally, compared with vehicle, the ratio of the wet lung weights to dry lung weights was significantly greater on exposure of animals to rottlerin; rottlerin also produced a dose-dependent increase in EBD extravasation into the lungs. These effects on lung edema occurred without any increase in right ventricular pressures. Microscopic assessment of edema in the ex vivo lungs demonstrated perivascular cuffing, with no evidence of septal capillary leak, in rottlerin-exposed lungs. Taken together, rottlerin increases barrier dysfunction in pulmonary endothelial cell monolayers and causes pulmonary edema in rats; results suggestive of an important role for PKC delta in maintaining lung endothelial barrier function.