Manitsopoulos Nikolaos, Orfanos Stylianos E, Kotanidou Anastasia, Nikitopoulou Ioanna, Siempos Ilias, Magkou Christina, Dimopoulou Ioanna, Zakynthinos Spyros G, Armaganidis Apostolos, Maniatis Nikolaos A
Respir Res. 2015 Feb 14;16(1):24. doi: 10.1186/s12931-015-0173-y.
Mortality from severe acute respiratory distress syndrome exceeds 40% and there is no available pharmacologic treatment. Mechanical ventilation contributes to lung dysfunction and mortality by causing ventilator-induced lung injury. We explored the utility of simvastatin in a mouse model of severe ventilator-induced lung injury.
Male C57BL6 mice (n = 7/group) were pretreated with simvastatin or saline and received protective (8 mL/kg) or injurious (25 mL/kg) ventilation for four hours. Three doses of simvastatin (20 mg/kg) or saline were injected intraperitoneally on days -2, -1 and 0 of the experiment. Lung mechanics, (respiratory system elastance, tissue damping and airway resistance), were evaluated by forced oscillation technique, while respiratory system compliance was measured with quasi-static pressure-volume curves. A pathologist blinded to treatment allocation scored hematoxylin-eosin-stained lung sections for the presence of lung injury. Pulmonary endothelial dysfunction was ascertained by bronchoalveolar lavage protein content and lung tissue expression of endothelial junctional protein Vascular Endothelial cadherin by immunoblotting. To assess the inflammatory response in the lung, we determined bronchoalveolar lavage fluid total cell content and neutrophil fraction by microscopy and staining in addition to Matrix-Metalloprotease-9 by ELISA. For the systemic response, we obtained plasma levels of Tumor Necrosis Factor-α, Interleukin-6 and Matrix-Metalloprotease-9 by ELISA. Statistical hypothesis testing was undertaken using one-way analysis of variance and Tukey's post hoc tests.
Ventilation with high tidal volume (HVt) resulted in significantly increased lung elastance by 3-fold and decreased lung compliance by 45% compared to low tidal volume (LVt) but simvastatin abrogated lung mechanical alterations of HVt. Histologic lung injury score increased four-fold by HVt but not in simvastatin-pretreated mice. Lavage pleocytosis and neutrophilia were induced by HVt but were significantly attenuated by simvastatin. Microvascular protein permeability increase 20-fold by injurious ventilation but only 4-fold with simvastatin. There was a 3-fold increase in plasma Tumor Necrosis Factor-α, a 7-fold increase in plasma Interleukin-6 and a 20-fold increase in lavage fluid Matrix-Metalloprotease-9 by HVt but simvastatin reduced these levels to control. Lung tissue vascular endothelial cadherin expression was significantly reduced by injurious ventilation but remained preserved by simvastatin.
High-dose simvastatin prevents experimental hyperinflation lung injury by angioprotective and anti-inflammatory effects.
严重急性呼吸窘迫综合征的死亡率超过40%，且尚无可用的药物治疗方法。机械通气会导致呼吸机诱导的肺损伤，进而造成肺功能障碍和死亡。我们在严重呼吸机诱导的肺损伤小鼠模型中探究了辛伐他汀的作用。
雄性C57BL6小鼠（每组n = 7只）分别用辛伐他汀或生理盐水预处理，然后接受4小时的保护性通气（8毫升/千克）或损伤性通气（25毫升/千克）。在实验的第 -2、-1和0天，腹腔注射三剂辛伐他汀（20毫克/千克）或生理盐水。通过强迫振荡技术评估肺力学（呼吸系统弹性、组织阻尼和气道阻力），同时用准静态压力-容积曲线测量呼吸系统顺应性。一位对治疗分配不知情的病理学家对苏木精-伊红染色的肺切片进行评分，以确定是否存在肺损伤。通过支气管肺泡灌洗蛋白含量和免疫印迹法检测肺组织内皮连接蛋白血管内皮钙黏蛋白的表达，以确定肺内皮功能障碍。为评估肺内的炎症反应，我们通过显微镜检查、染色以及酶联免疫吸附测定法（ELISA）检测支气管肺泡灌洗液中的总细胞含量、中性粒细胞比例以及基质金属蛋白酶-9。对于全身反应，我们通过ELISA检测血浆中肿瘤坏死因子-α、白细胞介素-6和基质金属蛋白酶-9的水平。采用单因素方差分析和Tukey事后检验进行统计假设检验。
与低潮气量（LVt）通气相比，高潮气量（HVt）通气使肺弹性显著增加3倍，肺顺应性降低45%，但辛伐他汀消除了HVt引起的肺力学改变。HVt使组织学肺损伤评分增加了4倍，但在辛伐他汀预处理的小鼠中未出现这种情况。HVt诱导了灌洗细胞增多和中性粒细胞增多，但辛伐他汀使其显著减轻。损伤性通气使微血管蛋白通透性增加20倍，但使用辛伐他汀时仅增加4倍。HVt使血浆肿瘤坏死因子-α增加3倍，血浆白细胞介素-6增加7倍，灌洗液中基质金属蛋白酶-9增加20倍，但辛伐他汀将这些水平降至对照水平。损伤性通气使肺组织血管内皮钙黏蛋白表达显著降低，但辛伐他汀使其得以保留。
高剂量辛伐他汀通过血管保护和抗炎作用预防实验性过度充气性肺损伤。
