Stimulation of Rho signaling by pathologic mechanical stretch is a "second hit" to Rho-independent lung injury induced by IL-6
Stimulation of Rho signaling by pathologic mechanical stretch is a "second hit" to Rho-independent lung injury induced by IL-6
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DOI：
10.1152/ajplung.00292.2011
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发表时间：
2012-05-01
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.;Tian, Yufeng;Birukov, Konstantin G.
毕鲁可娃A，田毅，Meliton A, Leff A，吴涛，比鲁可夫KG。病理性机械拉伸刺激Rho信号是对IL-6诱导的Rho非依赖性肺损伤的“二次打击”。[J] .中国生物医学工程学报，2016,31(2):444 - 444。2012年2月17日首次出版；doi: 10.1152 / ajplung.00292.2011。-大多数急性肺损伤（ALI）及脓毒性和非脓毒性急性呼吸窘迫综合征患者需要辅助正压通气，在次优通气范围内可能进一步加重肺功能障碍。先前的研究描述了激动剂诱导的Rho GTPase信号传导和内皮细胞（EC）通透性在暴露于病理相关的循环拉伸（CS）量级的EC培养中增强。本研究检测了病理性CS在IL-6引起的肺EC通透性调节中的作用，IL-6是一种在败血症中增加的细胞因子，以rho独立的方式起作用。IL-6增加了EC的通透性，这与Jak/信号转导器和转录激活因子、p38 MAP激酶和NF-kappa B信号的激活有关，并在EC暴露于18% CS时增强。Rho激酶抑制剂Y-27632抑制了18% CS对IL-6诱导的EC单层破坏的协同作用，但没有改变IL-6对静态EC培养的影响。18% CS通过肺EC和中性粒细胞粘附增加il -6诱导的ICAM-1表达，Y-27632可减弱这种表达。C57BL/6J小鼠气管内注射IL-6可提高支气管肺泡灌洗液蛋白含量和细胞计数。高潮气量机械通气（HTV; 30 ml/kg, 4 h）增强了这些变化。静脉注射Y-27632可抑制IL6/ htv诱导的肺损伤。总之，本研究提出了一种促成ALI双击模型的新机制：除了凝血酶、TNF α、LPS或其他激动剂对Rho依赖性内皮细胞高通透性的协同作用外，呼吸机诱导的肺损伤相关CS还可能通过涉及Rho活性的机制，加剧其他炎症介质如IL-6诱导的Rho非依赖性EC通透性机制。
Birukova AA, Tian Y, Meliton A, Leff A, Wu T, Birukov KG. Stimulation of Rho signaling by pathologic mechanical stretch is a "second hit" to Rho-independent lung injury induced by IL-6. Am J Physiol Lung Cell Mol Physiol 302: L965-L975, 2012. First published February 17, 2012; doi: 10.1152/ajplung.00292.2011.-Most patients with acute lung injury (ALI) and acute respiratory distress syndrome of septic and nonseptic nature require assisted ventilation with positive pressure, which at suboptimal range may further exacerbate lung dysfunction. Previous studies described enhancement of agonist-induced Rho GTPase signaling and endothelial cell (EC) permeability in EC cultures exposed to pathologically relevant cyclic stretch (CS) magnitudes. This study examined a role of pathologic CS in modulation of pulmonary EC permeability caused by IL-6, a cytokine increased in sepsis and acting in a Rho-independent manner. IL-6 increased EC permeability, which was associated with activation of Jak/signal transducers and activators of transcription, p38 MAP kinase, and NF-kappa B signaling and was augmented by EC exposure to 18% CS. Rho kinase inhibitor Y-27632 suppressed the synergistic effect of 18% CS on IL-6-induced EC monolayer disruption but did not alter the IL-6 effects on static EC culture. 18% CS also increased IL-6-induced ICAM-1 expression by pulmonary EC and neutrophil adhesion, which was attenuated by Y-27632. Intratracheal IL-6 administration in C57BL/6J mice increased protein content and cell count in bronchoalveolar lavage fluid. These changes were augmented by high tidal volume mechanical ventilation (HTV; 30 ml/kg, 4 h). Intravenous injection of Y-27632 suppressed IL6/HTV-induced lung injury. In conclusion, this study proposes a novel mechanism contributing to two-hit model of ALI: in addition to synergistic effects on Rho-dependent endothelial hyper-permeability triggered by thrombin, TNF alpha, LPS, or other agonists, ventilator-induced lung injury-relevant CS may also exacerbate Rho-independent mechanisms of EC permeability induced by other inflammatory mediators such as IL-6 via mechanisms involving Rho activity.