Shanghai Key Laboratory of Signaling and Disease Research, Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Department of Nephropathy, Shanghai Seventh People's Hospital, Shanghai, China.
Eur J Pharmacol. 2021 Dec 15;913:174643. doi: 10.1016/j.ejphar.2021.174643. Epub 2021 Nov 19.
Sepsis is considered as a life-threatening organ dysfunction caused by a dysregulated response of the host to an infection. Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening condition, and is the type of organ injury that is most commonly induced by sepsis. Resveratrol (RSV) has been shown to exert a wide range of therapeutic effects due to its anti-inflammatory and anti-oxidant properties. The present study aimed to investigate whether RSV could mitigate sepsis-induced ALI/ARDS, and also to unravel the underlying mechanism. The model of sepsis was established by applying the cecal ligation and puncture (CLP) method, and mitochondria from the lung tissue were isolated to assess mitochondrial function, as determined from measuring mitochondrial superoxide production using MitoSOX red mitochondrial superoxide indicator and the membrane potential. It was found that RSV could exert a protective role in CLP-induced ALI/ARDS, as evidenced by moderate levels of inflammatory cell infiltration and interstitial edema, as well as decreased levels of C-reactive protein (P<0.01), interleukin (IL)-6 (P<0.01), IL-1β (P<0.01) and tumor necrosis factor-α (P<0.01). Moreover, phospholipid scramblase 3 (PLSCR-3)-mediated mitochondrial dysfunction and mitophagy were shown to contribute towards the CLP-caused lung damage, which was reversed upon RSV administration, as demonstrated by improved mitochondrial function and markedly reduced increases in the protein levels of autophagy related (ATG)5 (P<0.01), ATG7 (P<0.05) and microtubule-associated protein 1A/1B-light chain 3 (LC3-Ⅰ/Ⅱ) (P<0.01), and a significantly increased expression of P62 (P<0.05). In addition, with regard to the CLP-induced lung injury in the mouse model, overexpression of PLSCR-3 was found to remove the beneficial effects observed upon RSV treatment. Taken together, the results of the present study have uncovered a novel molecular mechanism through which RSV may alleviate ALI/ARDS via regulating PLSCR-3-mediated mitochondrial dysfunction and mitophagy in CLP-induced mouse model.
脓毒症被认为是一种危及生命的器官功能障碍，是由宿主对感染的失调反应引起的。急性肺损伤（ALI）/急性呼吸窘迫综合征（ARDS）是一种危及生命的病症，是最常由脓毒症引起的器官损伤类型。白藜芦醇（RSV）由于其抗炎和抗氧化特性，已被证明具有广泛的治疗效果。本研究旨在探讨 RSV 是否可以减轻脓毒症引起的 ALI/ARDS，并揭示其潜在机制。通过应用盲肠结扎和穿刺（CLP）方法建立脓毒症模型，并分离肺组织中的线粒体，以评估线粒体功能，通过使用 MitoSOX red 线粒体超氧化物指示剂测量线粒体超氧化物产生和膜电位来确定。结果发现，RSV 可以在 CLP 诱导的 ALI/ARDS 中发挥保护作用，表现为炎症细胞浸润和间质水肿程度适中，C-反应蛋白（P<0.01）、白细胞介素（IL）-6（P<0.01）、IL-1β（P<0.01）和肿瘤坏死因子-α（P<0.01）水平降低。此外，磷脂翻转酶 3（PLSCR-3）介导的线粒体功能障碍和自噬被证明有助于 CLP 引起的肺损伤，而 RSV 给药后则逆转了这种损伤，表现为线粒体功能改善，自噬相关（ATG）5（P<0.01）、ATG7（P<0.05）和微管相关蛋白 1A/1B-轻链 3（LC3-Ⅰ/Ⅱ）（P<0.01）的蛋白水平增加明显减少，P62（P<0.05）的表达显著增加。此外，在 CLP 诱导的小鼠模型中，发现 PLSCR-3 的过表达消除了 RSV 治疗观察到的有益作用。综上所述，本研究结果揭示了 RSV 通过调节 CLP 诱导的小鼠模型中 PLSCR-3 介导的线粒体功能障碍和自噬来缓解 ALI/ARDS 的新分子机制。
