Wang Lei, Li Hai-Dong, Sun Xia, Ni Jia-Hui, Feng Gui-Ze, Shen Xiao-Yan, Weng Hong-Bo, Fang Hao
Department of Pharmacology, School of Pharmacy, Fudan University, No. 826, Zhangheng Road, Pudong New Area, Shanghai, 201203, China.
Research and Translational Laboratory of Acute Injury and Secondary Infection, Minhang Hospital, Fudan University, Shanghai, China.
Inflammation. 2025 Apr 7. doi: 10.1007/s10753-025-02293-6.
Acute lung injury (ALI), which can progress to acute respiratory distress syndrome (ARDS), has inflammation as a crucial factor, especially the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome involvement. Stromal interaction molecule 1 (STIM1) can block NLRP3 activation, but the mechanism is unclear. Vanillic acid, possessing anti-inflammatory properties, has a role in acute lung injury (ALI) whose specific mechanism remains unclear. This study aimed to investigate the effectiveness of vanillic acid in ALI induced by lipopolysaccharides (LPS) and to elucidate the potential mechanisms. In vitro and in vivo experiments were conducted using cells and a mouse model to find out the impact and underlying mechanisms. We found that vanillic acid demonstrated significant inhibition of IL-1β and IL-18 release triggered by LPS and nigericin in J774A.1 cells. The in vivo findings indicated that vanillic acid not only mitigated acute lung injury but also suppressed NLRP3 inflammasome activation in mice. Mechanistically, vanillic acid inhibited the LPS-induced increase in STIM1 expression through the lysosomal degradation pathway. The reduced STIM1 expression diminished intracellular Ca levels, thereby suppressing inflammasome activation and impeding the cleavage and maturation of Caspase-1 and GSDMD, and eventually attenuating cell pyroptosis. Vanillic acid exerts its inhibitory effects on NLRP3 inflammasome activation by promoting STIM1 degradation, thereby ameliorates ALI through impeding NLRP3-GSDMD mediated pyroptosis. The STIM1-NLRP3 signaling axis represents a promising avenue for potential therapeutic interventions in ALI.
急性肺损伤（ALI）可进展为急性呼吸窘迫综合征（ARDS），炎症是其关键因素，尤其是NOD样受体热蛋白结构域相关蛋白3（NLRP3）炎性小体的参与。基质相互作用分子1（STIM1）可阻断NLRP3激活，但其机制尚不清楚。具有抗炎特性的香草酸在急性肺损伤（ALI）中起作用，但其具体机制仍不清楚。本研究旨在探讨香草酸对脂多糖（LPS）诱导的ALI的有效性，并阐明其潜在机制。使用细胞和小鼠模型进行了体外和体内实验，以找出其影响和潜在机制。我们发现香草酸对LPS和尼日利亚菌素在J774A.1细胞中触发的IL-1β和IL-18释放具有显著抑制作用。体内研究结果表明，香草酸不仅减轻了急性肺损伤，还抑制了小鼠体内NLRP3炎性小体的激活。机制上，香草酸通过溶酶体降解途径抑制LPS诱导的STIM1表达增加。STIM1表达的降低使细胞内钙水平降低，从而抑制炎性小体激活，阻碍半胱天冬酶-1和Gasdermin D（GSDMD）的切割和成熟，最终减轻细胞焦亡。香草酸通过促进STIM1降解对NLRP3炎性小体激活发挥抑制作用，从而通过阻碍NLRP3-GSDMD介导的焦亡改善ALI。STIM1-NLRP3信号轴是ALI潜在治疗干预的一个有前景的途径。
