Maniatis Nikolaos A, Harokopos Vaggelis, Thanassopoulou Artemis, Oikonomou Nikos, Mersinias Vassilis, Witke Walter, Orfanos Stylianos E, Armaganidis Apostolos, Roussos Charalambos, Kotanidou Anastasia, Aidinis Vassilis
Marianthi Simou Lab, Evaggelismos Hospital, University of Athens Medical School, Athens, Greece.
Am J Respir Cell Mol Biol. 2009 Oct;41(4):426-32. doi: 10.1165/rcmb.2008-0144OC. Epub 2009 Feb 6.
Mechanical ventilation, an essential life-support modality of patients with acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS), exerts its detrimental effects through largely unknown mechanisms. Gelsolin (GSN), an actin-binding protein and a substrate of caspase-3, was recently shown to play a major role in bleomycin- or lipopolysaccharide-induced lung injury. To dissect a possible role of GSN in the pathogenesis of ventilator-induced lung injury (VILI), genetically modified mice lacking GSN expression and wild-type controls underwent mechanical ventilation with high tidal volumes. GSN was found up-regulated in the airways upon VILI, and its genetic ablation led to almost complete disease protection as manifested by reduced edema formation, reduced lung injury, attenuated epithelial apoptosis, diminished cytokine expression, and impaired neutrophil infiltration. GSN fragmentation was shown to be an effector mechanism in VILI-induced apoptosis, while GSN expression was shown to be necessary for efficient neutrophil infiltration, which was found to be a prerequisite for VILI induction in this model. Therefore, intracellular GSN and GSN-mediated responses were shown to be an important player in the pathogenesis of VILI.
机械通气是急性肺损伤（ALI）或急性呼吸窘迫综合征（ARDS）患者重要的生命支持方式，但其有害作用的机制很大程度上尚不清楚。凝溶胶蛋白（GSN）是一种肌动蛋白结合蛋白，也是半胱天冬酶-3的底物，最近研究表明其在博来霉素或脂多糖诱导的肺损伤中起主要作用。为了剖析GSN在呼吸机诱导性肺损伤（VILI）发病机制中的可能作用，对缺乏GSN表达的基因改造小鼠和野生型对照小鼠进行了高潮气量机械通气。发现VILI时气道中GSN上调，其基因缺失导致几乎完全的疾病保护，表现为水肿形成减少、肺损伤减轻、上皮细胞凋亡减弱、细胞因子表达降低以及中性粒细胞浸润受损。GSN片段化被证明是VILI诱导的细胞凋亡中的一种效应机制，而GSN表达被证明是有效中性粒细胞浸润所必需的，中性粒细胞浸润是该模型中VILI诱导的一个先决条件。因此，细胞内GSN和GSN介导的反应被证明是VILI发病机制中的一个重要因素。
