Department of Pulmonary Medicine, Clinical Center for Sleep Breathing and Snoring, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
Department of Pulmonary Medicine, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, 310006, China.
Acta Pharmacol Sin. 2019 May;40(5):630-641. doi: 10.1038/s41401-018-0045-3. Epub 2018 Jul 18.
The integrity of the endothelial barrier is a determinant of the prognosis of lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, we investigated whether and how Sirtuin 1 (SIRT1) maintained the vascular integrity during ALI. An experimental model of ALI was established in mice through intratracheal administration of LPS (10 mg/kg). LPS stimulation significantly increased the pulmonary permeability and decreased the expression of SIRT1 and tight junction proteins (TJs), including occludin, claudin-5, tight junction protein 1 and tight junction protein 2. Morphological studies showed that LPS induced obvious lung injury with inflammatory cell infiltration in the interstitial and alveolar space, hemorrhage, edema, and the thickened alveolar wall compared to the control mice. Intratracheal administration of the selective SIRT1 activator SRT1720 (6.25 mg/kg) significantly attenuated LPS-induced lung injury, lung hyper-permeability and increased TJs expression, whereas intratracheal administration of the selective SIRT1 inhibitor EX527 (6.25 mg/kg) aggravated LPS-induced ALI. Similar protective effects of SIRT1 on pulmonary cellular permeability were observed in primary human pulmonary microvascular endothelial cells treated with LPS (2 mg/mL) in vitro. We further demonstrated that the RhoA/ROCK signaling pathway was activated in SIRT1 regulation of tight junction permeability. The RhoA/ROCK inhibitor Y-27632 (10 μM) increased the expression of TJs and reversed LPS- or EX527-induced hyper-permeability. In conclusion, SIRT1 ameliorates LPS-induced lung injury via decreasing endothelial tight junction permeability, possibly via RhoA/ROCK signaling pathway. This finding may contribute to the development of new therapeutic approaches for lung injury.
内皮屏障的完整性是脂多糖 (LPS) 诱导的急性肺损伤 (ALI) 预后的决定因素。在这项研究中，我们研究了 Sirtuin 1 (SIRT1) 是否以及如何在 ALI 期间维持血管完整性。通过气管内给予 LPS（10mg/kg）在小鼠中建立 ALI 实验模型。LPS 刺激显著增加了肺通透性，并降低了 SIRT1 和紧密连接蛋白 (TJs) 的表达，包括闭合蛋白、紧密连接蛋白 5、紧密连接蛋白 1 和紧密连接蛋白 2。形态学研究表明，与对照组小鼠相比，LPS 诱导明显的肺损伤，间质和肺泡空间有炎症细胞浸润、出血、水肿和肺泡壁增厚。气管内给予选择性 SIRT1 激活剂 SRT1720（6.25mg/kg）显著减轻 LPS 诱导的肺损伤、肺高通透性和增加 TJs 表达，而气管内给予选择性 SIRT1 抑制剂 EX527（6.25mg/kg）加重 LPS 诱导的 ALI。体外用 LPS（2mg/mL）处理的原代人肺微血管内皮细胞中也观察到 SIRT1 对肺细胞通透性的类似保护作用。我们进一步表明，RhoA/ROCK 信号通路在 SIRT1 调节紧密连接通透性中被激活。RhoA/ROCK 抑制剂 Y-27632（10μM）增加了 TJs 的表达，并逆转了 LPS 或 EX527 诱导的高通透性。总之，SIRT1 通过降低内皮紧密连接通透性来改善 LPS 诱导的肺损伤，可能通过 RhoA/ROCK 信号通路。这一发现可能有助于开发新的肺损伤治疗方法。
