RhoA inhibitor suppresses the production of microvesicles and rescues high ventilation induced lung injury
RhoA inhibitor suppresses the production of microvesicles and rescues high ventilation induced lung injury
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RhoA 抑制剂抑制微泡的产生并挽救高通气引起的肺损伤
DOI：
10.1016/j.intimp.2019.03.059
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发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Pan, Linghui
中科院分区：
文献类型：
--
作者：
Dai, Huijun;Zhang, Suisui;Pan, Linghui
微囊泡（Microvesicles，MV）广泛存在于支气管肺泡灌洗液（Bronchoalveolar lavage fluid，BALF）、外周血和腹水中。我们以前的研究表明，MVs是急性肺损伤的原因，但MVs形成的确切机制仍然知之甚少。在本研究中，我们研究了RhoA/Rock信号转导在MVs产生中的潜在作用以及MVs在呼吸机诱导的肺损伤（VILI）中的生物学活性。我们的研究结果表明，高潮通气诱导超级MV释放到肺部，随后引起肺部炎症。引人注目的是，从高度通气的小鼠中分离的MV的气管内滴注在幼稚小鼠中引发显著的肺部炎症。MVs的产生与肺部炎症以及RhoA、Rock和磷酸化Limk（Limk的磷酸化是活化形式）的上调强烈相关。RhoA抑制剂可降低Rock的表达和Limk的磷酸化，减少MVs的产生，减轻肺炎症。Rock抑制剂还降低Limk的磷酸化，减少MVs的产生并减轻肺部炎症。我们的数据表明，MVs的产生需要RhoA/Rock信号传导，并且VILI可能通过靶向RhoA/Rock信号传导途径而被潜在地预防。
Microvesicles (MVs) have been extensively identified in various biological fluids including bronchoalveolar lavage fluid (BALF), peripheral blood and ascitic fluids. Our previous study showed that MVs are responsible for acute lung injury, but the exact mechanism underlying MVs formation remains poorly understood. In the present study, we investigate the potential role of RhoA/Rock signaling in MVs generation and the biological activity of MVs in ventilator-induced lung injury (VILI). Our results revealed that high tide ventilation induced super MVs releasing into the lung and subsequently caused lung inflammation. Strikingly, intratracheal instillation of MVs that isolated from highly ventilated mice triggered significant lung inflammation in naive mice. The MVs production is strongly correlated with lung inflammation and the upregulation of RhoA, Rock and phospho-Limk (phosphorylation of Limk is the activated form). RhoA inhibitor decreased the expression of Rock and the phosphorylation of Limk, decreased MVs production and alleviated lung inflammation. Rock inhibitor also decreased the phosphorylation of Limk, decreased MVs production and alleviated lung inflammation. Our data demonstrated that the production of MVs requires RhoA/Rock signaling, and VILI might be potentially prevented by targeting RhoA/Rock signaling pathway.