瑞舒伐他汀通过PI3K/AKT/Nedd4-2信号通路激活钠通道和钠钾ATP酶的表达，从而增强脂多糖诱导的急性肺损伤中的肺泡液体清除能力。
Rosuvastatin Enhances Alveolar Fluid Clearance in Lipopolysaccharide-Induced Acute Lung Injury by Activating the Expression of Sodium Channel and Na,K-ATPase via the PI3K/AKT/Nedd4-2 Pathway.
作者信息
Xu Hao-Ran, Yang Qian, Xiang Shu-Yang, Zhang Pu-Hong, Ye Yang, Chen Yan, Xu Ke-Wen, Ren Xi-Ya, Mei Hong-Xia, Shen Chen-Xi, Ma Hong-Yu, Smith Fang-Gao, Jin Sheng-Wei, Wang Qian
机构信息
Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People's Republic of China.
Wenzhou Medical University, Wenzhou, People's Republic of China.
出版信息
J Inflamm Res. 2021 Apr 16;14:1537-1549. doi: 10.2147/JIR.S299267. eCollection 2021.
BACKGROUND
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are devastating clinical conditions characterized by pulmonary epithelial damage and protein-rich fluid accumulation in the alveolar spaces. Statins are a class of HMG-CoA reductase inhibitors, which exert cholesterol-lowering and anti-inflammatory effects.
METHODS
Rosuvastatin (1 mg/kg) was injected intravenously in rats 12 h before lipopolysaccharide (LPS, 10 mg/kg) administration. Eight hours later after LPS challenge, alveolar fluid clearance (AFC) was detected in rats (n = 6-8). Rosuvastatin (0.3 µmol/mL) and LPS were cultured with primary rat alveolar type II epithelial cells for 8 h.
RESULTS
Rosuvastatin obviously improved AFC and attenuated lung-tissue damage in ALI model. Moreover, it enhanced AFC by increasing sodium channel and Na,K-ATPase protein expression. It also up-regulated P-Akt via reducing Nedd4-2 in vivo and in vitro. Furthermore, LY294002 blocked the increase in AFC in response to rosuvastatin. Rosuvastatin-induced AFC was found to be partly rely on sodium channel and Na,K-ATPase expression via the PI3K/AKT/Nedd4-2 pathway.
CONCLUSION
In summary, the findings of our study revealed the potential role of rosuvastatin in the management of ALI/ARDS.
背景
急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是具有毁灭性的临床病症，其特征为肺上皮损伤和肺泡腔内富含蛋白质的液体蓄积。他汀类药物是一类HMG-CoA还原酶抑制剂，具有降低胆固醇和抗炎作用。
方法
在给予脂多糖（LPS，10mg/kg）前12小时，给大鼠静脉注射瑞舒伐他汀（1mg/kg）。LPS攻击8小时后，检测大鼠（n = 6 - 8）的肺泡液体清除率（AFC）。将瑞舒伐他汀（0.3μmol/mL）和LPS与原代大鼠II型肺泡上皮细胞共培养8小时。
结果
瑞舒伐他汀明显改善了ALI模型中的AFC并减轻了肺组织损伤。此外，它通过增加钠通道和Na，K-ATP酶蛋白表达来增强AFC。它还通过在体内和体外减少Nedd4-2来上调P-Akt。此外，LY294002阻断了瑞舒伐他汀引起的AFC增加。发现瑞舒伐他汀诱导的AFC部分依赖于通过PI3K/AKT/Nedd4-2途径的钠通道和Na，K-ATP酶表达。
结论
总之，我们的研究结果揭示了瑞舒伐他汀在ALI/ARDS治疗中的潜在作用。
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