Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, 610041 Sichuan Province, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041 Sichuan Province, China.
Mediators Inflamm. 2021 Dec 21;2021:9247285. doi: 10.1155/2021/9247285. eCollection 2021.
Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor and inhibits cholesterol synthesis. Recently, atorvastatin also showed anti-inflammatory effect in acute lung injury, ameliorating pulmonary gas-blood exchanging function. Sphingosine kinase 1 plays a central role in endothelial (EC) cytoskeleton rearrangement and EC barrier integrity regulation. In this study, the role of sphingosine kinase 1 in atorvastatin anti-inflammatory effect against acute lung injury was investigated. Both wild-type (WT) and SphK1 mice were challenged with high tidal volume ventilation (40 ml/kg body weight, 65 breathing/min, 4 hours). The acute lung injury was evaluated and the mechanisms were explored. In WT mice, atorvastatin treatment significantly decreased acute lung injury responding to high tidal volume ventilation (HT), including protein, cellular infiltration, and cytokine releasing; comparing to WT mice, SphK1 mice showed significantly worsen pulmonary injuries on HT model. Moreover, the atorvastatin-mediated anti-inflammatory effect was diminished in SphK1 mice. To further confirm the role of SphK1 in VILI, we then compared the inflammatory response of endothelial cells that were isolated from WT and SphK1 mice to cyclic stretching. Similarly, atorvastatin significantly decreased cytokine generation from WT EC responding to cyclic stretching. Atorvastatin also significantly preserved endothelial junction integrity in WT EC against thrombin challenge. However, the inhibitory effect of atorvastatin on cytokine generation induced by cyclic stretching was abolished on SphK1 mice EC. The endothelial junction integrity effects of atorvastatin also diminished on SphK1 mouse EC. Signal analysis indicated that atorvastatin inhibited JNK activation induced by cyclic stretch. SphK1 knockout also blocked atorvastatin-mediated VE-cadherin junction enhancement. In summary, by inhibition of MAPK activity and maintenance of EC junction homeostasis, SphK1 plays a critical role in atorvastatin-mediated anti-inflammatory effects in both cellular and in vivo model. This study also offers an insight into mechanical stress-mediated acute lung injury and potential therapy in the future.
阿托伐他汀是 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMG-CoA 还原酶）抑制剂，可抑制胆固醇合成。最近，阿托伐他汀在急性肺损伤中也表现出抗炎作用，改善肺气血交换功能。鞘氨醇激酶 1（SphK1）在血管内皮细胞（EC）细胞骨架重排和 EC 屏障完整性调节中起核心作用。在这项研究中，研究了 SphK1 在阿托伐他汀抗急性肺损伤中的作用。使用野生型（WT）和 SphK1 小鼠进行大潮气量通气（40ml/kg 体重，65 次/分钟，4 小时）挑战。评估急性肺损伤，并探讨其机制。在 WT 小鼠中，阿托伐他汀治疗显著降低了对大潮气量通气（HT）的急性肺损伤反应，包括蛋白、细胞浸润和细胞因子释放；与 WT 小鼠相比，SphK1 小鼠在 HT 模型上表现出明显更严重的肺损伤。此外，SphK1 小鼠中阿托伐他汀介导的抗炎作用减弱。为了进一步证实 SphK1 在 VILI 中的作用，我们比较了 WT 和 SphK1 小鼠分离的内皮细胞对周期性拉伸的炎症反应。同样，阿托伐他汀显著降低了 WT 内皮细胞对周期性拉伸的细胞因子生成。阿托伐他汀还显著保存了 WT 内皮细胞在凝血酶挑战下的内皮连接完整性。然而，阿托伐他汀对 SphK1 小鼠内皮细胞中周期性拉伸诱导的细胞因子生成的抑制作用被消除。阿托伐他汀对 SphK1 小鼠内皮细胞的内皮连接完整性效应也减弱。信号分析表明，阿托伐他汀抑制了由周期性拉伸引起的 JNK 激活。SphK1 敲除也阻断了阿托伐他汀介导的 VE-钙粘蛋白连接增强。综上所述，通过抑制 MAPK 活性和维持 EC 连接的稳定性，SphK1 在细胞和体内模型中阿托伐他汀介导的抗炎作用中起关键作用。这项研究还为机械应激介导的急性肺损伤和未来的潜在治疗提供了新的见解。
