Institute of Chinese Materia Madica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
Department of Pharmacy, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
Int Immunopharmacol. 2023 Dec;125(Pt B):111161. doi: 10.1016/j.intimp.2023.111161. Epub 2023 Nov 9.
Acute lung injury (ALI), a progressive lung disease mostly caused by sepsis, is characterized by uncontrolled inflammatory responses, increased oxidative stress, pulmonary barrier dysfunction, and pulmonary edema. Ursodeoxycholic acid (UDCA) is a natural bile acid with various pharmacological properties and is extensively utilized in clinical settings for the management of hepatobiliary ailments. Nonetheless, the potential protective effects and mechanism of UDCA on sepsis-induced lung injuries remain unknown. In this study, we reported that UDCA effectively inhibited pulmonary edema, inflammatory cell infiltration, pro-inflammatory cytokines production, and oxidative stress. Furthermore, UDCA treatment significantly alleviated the damage of pulmonary barrier and enhanced alveolar fluid clearance. Importantly, UDCA treatment potently suppressed PANoptosis-like cell death which is demonstrated by the block of apoptosis, pyroptosis, and necroptosis. Mechanistically, UDCA treatment prominently inhibited STING pathway. And the consequential loss of STING substantially impaired the beneficial effects of UDCA treatment on the inflammatory response, pulmonary barrier, and PANoptosis. These results indicate that STING plays a pivotal role in the UDCA treatment against sepsis-induced lung injury. Collectively, our findings show that UDCA treatment can ameliorate sepsis-induced lung injury and verified a previously unrecognized mechanism by which UDCA alleviated sepsis-induced lung injury through blocking PANoptosis-like cell death via STING pathway.
急性肺损伤（ALI），一种主要由脓毒症引起的进行性肺部疾病，其特征为不受控制的炎症反应、氧化应激增加、肺屏障功能障碍和肺水肿。熊去氧胆酸（UDCA）是一种具有多种药理特性的天然胆酸，广泛应用于临床治疗肝胆疾病。然而，UDCA 对脓毒症引起的肺损伤的潜在保护作用和机制尚不清楚。在本研究中，我们报告 UDCA 能有效抑制肺水肿、炎性细胞浸润、促炎细胞因子产生和氧化应激。此外，UDCA 治疗显著减轻了肺屏障的损伤，并增强了肺泡液体清除。重要的是，UDCA 治疗能强力抑制 PANoptosis 样细胞死亡，这表现为凋亡、焦亡和坏死的阻断。机制上，UDCA 治疗显著抑制了 STING 通路。而 STING 的缺失显著损害了 UDCA 治疗对炎症反应、肺屏障和 PANoptosis 的有益作用。这些结果表明，STING 在 UDCA 治疗脓毒症性肺损伤中起着关键作用。总的来说，我们的研究结果表明，UDCA 治疗可以改善脓毒症引起的肺损伤，并验证了一个以前未被认识的机制，即 UDCA 通过阻断 STING 通路的 PANoptosis 样细胞死亡来减轻脓毒症引起的肺损伤。
