Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Chongqing Medical University, No.76 Linjiang Road, Yuzhong District, Chongqing, 400010, People's Republic of China.
J Transl Med. 2024 Jun 5;22(1):535. doi: 10.1186/s12967-024-05220-9.
Inflammation and endothelial barrier dysfunction are the major pathophysiological changes in acute respiratory distress syndrome (ARDS). Sphingosine-1-phosphate receptor 3 (S1PR3), a G protein-coupled receptor, has been found to mediate inflammation and endothelial cell (EC) integrity. However, the function of S1PR3 in ARDS has not been fully elucidated.
We used a murine lipopolysaccharide (LPS)-induced ARDS model and an LPS- stimulated ECs model to investigate the role of S1PR3 in anti-inflammatory effects and endothelial barrier protection during ARDS.
We found that S1PR3 expression was increased in the lung tissues of mice with LPS-induced ARDS. TY-52156, a selective S1PR3 inhibitor, effectively attenuated LPS-induced inflammation by suppressing the expression of proinflammatory cytokines and restored the endothelial barrier by repairing adherens junctions and reducing vascular leakage. S1PR3 inhibition was achieved by an adeno-associated virus in vivo and a small interfering RNA in vitro. Both the in vivo and in vitro studies demonstrated that pharmacological or genetic inhibition of S1PR3 protected against ARDS by inhibiting the NF-κB pathway and improving mitochondrial oxidative phosphorylation.
S1PR3 inhibition protects against LPS-induced ARDS via suppression of pulmonary inflammation and promotion of the endothelial barrier by inhibiting NF-κB and improving mitochondrial oxidative phosphorylation, indicating that S1PR3 is a potential therapeutic target for ARDS.
炎症和内皮屏障功能障碍是急性呼吸窘迫综合征（ARDS）的主要病理生理变化。鞘氨醇-1-磷酸受体 3（S1PR3）是一种 G 蛋白偶联受体，已被发现介导炎症和内皮细胞（EC）完整性。然而，S1PR3 在 ARDS 中的作用尚未完全阐明。
我们使用了脂多糖（LPS）诱导的 ARDS 小鼠模型和 LPS 刺激的 ECs 模型，以研究 S1PR3 在 ARDS 期间抗炎作用和内皮屏障保护中的作用。
我们发现 LPS 诱导的 ARDS 小鼠肺组织中 S1PR3 表达增加。S1PR3 选择性抑制剂 TY-52156 通过抑制促炎细胞因子的表达有效减轻 LPS 诱导的炎症，并通过修复黏附连接和减少血管渗漏来恢复内皮屏障。体内使用腺相关病毒和体外使用小干扰 RNA 实现了 S1PR3 抑制。体内和体外研究均表明，通过抑制 NF-κB 通路和改善线粒体氧化磷酸化，药理学或遗传学抑制 S1PR3 可预防 ARDS。
S1PR3 抑制通过抑制 NF-κB 和改善线粒体氧化磷酸化来抑制肺内炎症和促进内皮屏障，从而防止 LPS 诱导的 ARDS，这表明 S1PR3 是 ARDS 的潜在治疗靶点。
