Magnitude-dependent regulation of pulmonary endothelial cell barrier function by cyclic stretch
Magnitude-dependent regulation of pulmonary endothelial cell barrier function by cyclic stretch
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DOI：
10.1152/ajplung.00336.2002
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发表时间：
2003-10-01
影响因子：
4.9
通讯作者：
Garcia, JGN
中科院分区：
文献类型：
--
作者：
Birukov, KG;Jacobson, JR;Garcia, JGN
呼吸机诱导的肺损伤综合征的特征在于血管渗漏的显著增加和炎症过程的激活。为了探讨过度的周期性拉伸（CS）是否直接导致血管屏障破坏或增强内皮细胞对水肿剂的敏感性，将人肺动脉内皮细胞（HPAEC）暴露于生理学（5%伸长率）或病理学（18%伸长率）相关水平的应变。CS产生快速（10分钟）增加肌球蛋白轻链（MLC）磷酸化，激活p38和细胞外信号相关激酶1/2 MAP激酶，和肌动球蛋白重塑。急性（15分钟）和慢性（48小时）CS显着增强凝血酶诱导的MLC磷酸化（2.1倍和3.2倍，15分钟CS在5%和18%的伸长率和2.1倍和3.1倍，48小时CS在5%和18%的伸长率，分别）。HPAEC预处理在18%CS，但不是在5%CS，表现出显着增强凝血酶诱导的跨内皮电阻降低，但不影响屏障保护作用的鞘氨醇-1-磷酸（0.5 μ M）。最后，表达谱分析揭示了一些基因，包括小GT β，凋亡介质ZIP激酶和蛋白酶激活受体-2，以幅度依赖的方式由CS调节。因此，我们的研究表明CS的大小在调节激动剂介导的肺内皮细胞通透性中起关键作用，并强烈表明CS对HPAEC屏障特性的表型调节。
Ventilator-induced lung injury syndromes are characterized by profound increases in vascular leakiness and activation of inflammatory processes. To explore whether excessive cyclic stretch (CS) directly causes vascular barrier disruption or enhances endothelial cell sensitivity to edemagenic agents, human pulmonary artery endothelial cells (HPAEC) were exposed to physiologically (5% elongation) or pathologically (18% elongation) relevant levels of strain. CS produced rapid (10 min) increases in myosin light chain (MLC) phosphorylation, activation of p38 and extracellular signal-related kinase 1/2 MAP kinases, and actomyosin remodeling. Acute (15 min) and chronic (48 h) CS markedly enhanced thrombin-induced MLC phosphorylation (2.1-fold and 3.2-fold for 15-min CS at 5 and 18% elongation and 2.1-fold and 3.1-fold for 48-h CS at 5 and 18% elongation, respectively). HPAEC preconditioned at 18% CS, but not at 5% CS, exhibited significantly enhanced thrombin-induced reduction in transendothelial electrical resistance but did not affect barrier protective effect of sphingosine-1-phosphate (0.5 muM). Finally, expression profiling analysis revealed a number of genes, including small GTPase rho, apoptosis mediator ZIP kinase, and proteinase activated receptor-2, to be regulated by CS in an amplitude-dependent manner. Thus our study demonstrates a critical role for the magnitude of CS in regulation of agonist-mediated pulmonary endothelial cell permeability and strongly suggests phenotypic regulation of HPAEC barrier properties by CS.