Successful Treatment of Acute Lung Injury with Pitavastatin in Septic Mice: Potential Role of Glucocorticoid Receptor Expression in Alveolar Macrophages
Successful Treatment of Acute Lung Injury with Pitavastatin in Septic Mice: Potential Role of Glucocorticoid Receptor Expression in Alveolar Macrophages
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DOI：
10.1124/jpet.110.171462
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发表时间：
2011-02
影响因子：
3.5
通讯作者：
Ken-ichi Takano;Seiji Yamamoto;K. Tomita;Michinori Takashina;H. Yokoo;N. Matsuda;Y. Takano;Y. Hattori
中科院分区：
文献类型：
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作者：
Ken-ichi Takano;Seiji Yamamoto;K. Tomita;Michinori Takashina;H. Yokoo;N. Matsuda;Y. Takano;Y. Hattori
越来越多的证据表明，HMG-CoA还原酶抑制剂（他汀类药物）提供了一些独立于其降脂作用的有益作用。最近的动物实验和临床试验表明，他汀类药物的使用可能限制败血症和相关全身炎症的发展。本研究的目的是探讨他汀类药物在预防治疗败血症引起的急性肺损伤（ALI）中的潜在作用。小鼠经盲肠结扎穿刺（CLP）致脓毒症。术前4天开始腹腔注射匹伐他汀3mg /kg / d，术后维持生命支持，可显著提高CLP小鼠的生存率。使用匹伐他汀治疗可以防止CLP小鼠ALI的发展，研究结果表明，严重低氧血症、肺血管通透性增加和包括炎症细胞浸润在内的组织学肺损伤得到了极大的改善。这与脓毒肺核因子-κB （NF-κB）活性升高的下调有关。虽然血浆皮质醇急剧升高，但肺中糖皮质激素受体（GCR）的表达在clp诱导的脓毒症发作后显著降低。值得注意的是，匹伐他汀增加GCR表达，并增加GCR所在的肺泡巨噬细胞，而不改变脓毒症相关的血浆皮质醇升高。这些结果证实了吡伐他汀对脓毒性ALI具有显著的保护作用，并表明随着肺泡巨噬细胞数量的增加，NF-κB活化下调与GCR表达增加相关，这可能部分解释了他汀类药物对ALI治疗有利的机制。
There is growing evidence that the HMG-CoA reductase inhibitors (statins) provide some of the beneficial effects that are independent of their lipid-lowering effects. Recent animal experiments and clinical trials suggest that statin use may limit the development of sepsis and associated systemic inflammation. The aim of this study was to explore the potential role of statins in the prevention treatment of sepsis-induced acute lung injury (ALI). Mice were rendered septic by cecal ligation and puncture (CLP). An intraperitoneal injection of 3 mg/kg per day of pitavastatin was initiated 4 days before surgery and was maintained for life support afterward, which significantly improved the survival of CLP mice. Treatment with pitavastatin prevented the ALI development in CLP mice, as indicated by the findings that severe hypoxemia, increased pulmonary vascular permeability, and histological lung damage, including inflammatory cell infiltrate, were greatly remedied. This was associated with down-regulation of increased activity of nuclear factor-κB (NF-κB) in septic lungs. Although plasma cortisol showed a sharp rise, glucocorticoid receptor (GCR) expression in the lungs was strikingly reduced after the onset of CLP-induced sepsis. It is noteworthy that pitavastatin increased GCR expression with an increase in alveolar macrophages in which GCRs are localized, without modifying the sepsis-associated rise in plasma cortisol. These results confirm significant protection by pitavastatin on septic ALI and demonstrate that down-regulated NF-κB activation associated with the GCR expression increase consequent to the increased number of alveolar macrophages may explain, in part, the mechanisms responsible for favorable effects of statins on the ALI management.