Zhai Yihui, Chen Kejie, Xu Zichuang, Chen Xiaojian, Tong Jiaying, He Yeying, Chen Chaoyue, Ding Meiqing, Liang Guang, Zheng Xiaohui
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
Respir Res. 2025 Mar 28;26(1):119. doi: 10.1186/s12931-025-03196-8.
Acute lung injury (ALI) is a life-threatening inflammatory lung disease that lacks safe and effective treatment strategies. Harmine, an alkaloid derived from Peganum harmala L plants, exhibits anti-inflammatory activity. However, the protective effect of harmine against ALI and its underlying mechanism remain unknown. This study aimed to elucidate the therapeutic effects and molecular mechanisms of harmine against ALI.
The therapeutic effects of harmine were assessed in LPS-induced ALI mice. Serum, bronchoalveolar lavage fluid (BALF), lung tissues were routinely analyzed to evaluated disease severity. The anti-inflammatory mechanism was elucidated in LPS-simulated RAW264.7 cells using a series assays, including RNA-seq, gene silencing, immunofluorescence, western blotting, co-immunoprecipitation and bioinformatic analysis. The biological safety of harmine was determined both in vitro and in vivo through cytotoxicity test, long-term cell proliferation test, acute toxicity test in mice, and assessments of liver and kidney function and structural changes.
The results showed that harmine inhibited the expression and secretion of LPS-induced inflammatory factors (IL-6, IL-1β and TNF-α) and reduced inflammatory cell infiltration in the lungs, resulting in alleviated LPS-induced histopathological changes and injury in mice. Mechanically, the findings revealed that harmine does not disrupt the TLR4-MD2 interaction but instead attenuates inflammation by suppressing CSF3 transcription and expression, leading to the inhibition of the MAPK/NF-κB signaling pathway activation induced by LPS stimulation. Additionally, both in vitro and in vivo studies demonstrated that harmine administration does not exhibit obvious cytotoxicity or long-term cell proliferation inhibition, nor does it cause functional or organic lesions the liver and kidney in mice, or other acute toxic effects.
These findings elucidated that the anti-inflammatory activity of harmine was achieved through the CSF3-mediated inactivation of the MAPK/NF-κB signaling pathway, suggesting that harmine could serve as a promising therapeutic drug for ALI and other inflammatory diseases.
急性肺损伤（ALI）是一种危及生命的炎症性肺病，缺乏安全有效的治疗策略。骆驼蓬碱是一种从骆驼蓬属植物中提取的生物碱，具有抗炎活性。然而，骆驼蓬碱对ALI的保护作用及其潜在机制尚不清楚。本研究旨在阐明骆驼蓬碱对ALI的治疗作用及其分子机制。
在脂多糖（LPS）诱导的ALI小鼠中评估骆驼蓬碱的治疗效果。对血清、支气管肺泡灌洗液（BALF）、肺组织进行常规分析以评估疾病严重程度。使用包括RNA测序、基因沉默、免疫荧光、蛋白质印迹、免疫共沉淀和生物信息学分析在内的一系列实验，在LPS模拟的RAW264.7细胞中阐明抗炎机制。通过细胞毒性试验、长期细胞增殖试验、小鼠急性毒性试验以及肝肾功能和结构变化评估，在体外和体内确定骆驼蓬碱的生物安全性。
结果表明，骆驼蓬碱抑制LPS诱导的炎症因子（IL-6、IL-1β和TNF-α）的表达和分泌，并减少肺内炎症细胞浸润，从而减轻LPS诱导的小鼠组织病理学变化和损伤。机制上，研究结果显示骆驼蓬碱不会破坏TLR4-MD2相互作用，而是通过抑制CSF3转录和表达来减轻炎症，从而抑制LPS刺激诱导的MAPK/NF-κB信号通路激活。此外，体外和体内研究均表明，给予骆驼蓬碱不会表现出明显的细胞毒性或长期细胞增殖抑制，也不会导致小鼠肝脏和肾脏的功能或器质性病变，或其他急性毒性作用。
这些研究结果阐明了骆驼蓬碱的抗炎活性是通过CSF3介导的MAPK/NF-κB信号通路失活实现的，表明骆驼蓬碱有望成为治疗ALI和其他炎症性疾病的药物。
