Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury
Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury
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DOI：
10.1152/ajplung.00354.2004
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发表时间：
2005-06-01
影响因子：
4.9
通讯作者：
Garcia, JGN
中科院分区：
文献类型：
--
作者：
Jacobson, JR;Barnard, JW;Garcia, JGN
目前缺乏限制急性肺损伤（ALI）患者中观察到的危及生命的血管渗漏的治疗方法。我们探讨了辛伐他汀（一种3-羟基-3-甲基戊二酰（HMG）-CoA还原酶抑制剂，在体外介导内皮细胞屏障保护）在小鼠ALI炎症模型中的作用。C57 BL/6 J小鼠在24小时之前用辛伐他汀（5或20 mg/ kg体重，通过腹膜内注射）处理，并再次伴随着腹膜内施用LPS（2 μ g/ g体重）。炎症指数[24 h时经组织学证实评估的支气管肺泡灌洗（BAL）髓过氧化物酶活性和总中性粒细胞计数]在LPS单独给药后显著升高，但在接受辛伐他汀的小鼠中显著降低（20 mg/ kg;类似于降低35 - 60%）。辛伐他汀还降低了BAL白蛋白（类似于降低50%）和伊文思蓝白蛋白染料外渗至肺组织（100%），与屏障保护一致。最后，通过分析辛伐他汀诱导的基因表达（Affyestival平台）评估辛伐他汀介导的肺保护的持续性质。LPS介导的肺基因表达在许多基因本体中被辛伐他汀显著调节（例如，例如，在一个实施例中，炎症和免疫应答、NF-κ B调节）和与ALI的发展或严重性有关的单个基因（例如，例如，在一个实施例中，IL-6，Toll样受体4）。总之，这些发现证实了辛伐他汀对LPS诱导的肺血管渗漏和炎症的显著保护作用，并暗示了他汀类药物在ALI管理中的潜在作用。
Therapies to limit the life- threatening vascular leak observed in patients with acute lung injury (ALI) are currently lacking. We explored the effect of simvastatin, a 3-hydroxy-3-methylglutaryl ( HMG)-CoA reductase inhibitor that mediates endothelial cell barrier protection in vitro, in a murine inflammatory model of ALI. C57BL/6J mice were treated with simvastatin (5 or 20 mg/ kg body wt via intraperitoneal injection) 24 h before and again concomitantly with intratracheally administered LPS (2 mu g/ g body wt). Inflammatory indexes [bronchoalveolar lavage (BAL) myeloperoxidase activity and total neutrophil counts assessed at 24 h with histological confirmation] were markedly increased after LPS alone but significantly reduced in mice that also received simvastatin (20 mg/ kg; similar to 35 - 60% reduction). Simvastatin also decreased BAL albumin (similar to 50% reduction) and Evans blue albumin dye extravasation into lung tissue ( 100%) consistent with barrier protection. Finally, the sustained nature of simvastatin-mediated lung protection was assessed by analysis of simvastatin-induced gene expression (Affymetrix platform). LPS-mediated lung gene expression was significantly modulated by simvastatin within a number of gene ontologies ( e. g., inflammation and immune response, NF-kappa B regulation) and with respect to individual genes implicated in the development or severity of ALI (e. g., IL-6, Toll-like receptor 4). Together, these findings confirm significant protection by simvastatin on LPS- induced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI.