Wang Xinye, Wu Xinyu, Zhou Liqin, Lin Yuxi, Tang Zhiyi, Chen Chengshui, Wang Beibei, Lin Yuting
Department of Pulmonary and Critical Care Medicine, and Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Department of Pulmonary and Critical Care Medicine, and Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; The First School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Int Immunopharmacol. 2025 Aug 28;161:115003. doi: 10.1016/j.intimp.2025.115003. Epub 2025 Jun 9.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by inflammation and fibrosis. Demethyleneberberine (DMB), a natural compound derived from traditional Chinese medicine, possesses both anti-inflammatory and antifibrotic properties. This study investigated the therapeutic potential of DMB in pulmonary fibrosis and elucidated its underlying mechanisms of action.
Pulmonary fibrosis was induced in male C57BL/6 mice via intratracheal administration of bleomycin (BLM, 1.5 mg/kg). The mice were randomly assigned to four groups (n = 10 per group): control, BLM, BLM + DMB (5 mg/kg), and BLM + DMB (10 mg/kg). An in vitro model of pulmonary fibrosis was established by stimulating MLE-12 cells with transforming growth factor-β1 (TGF-β1, 5 ng/mL). Lung structural and functional changes were assessed using hematoxylin and eosin staining, lung-function testing, and micro-computed tomography. The relationship between NLRP3 and EMT during the process of DMB alleviating pulmonary fibrosis was further explored by inducing NLRP3 overexpression in vitro.
DMB treatment significantly alleviated histopathological alterations and reduced collagen deposition in lung tissues. It also inhibited activation of both the canonical and non-canonical NLRP3 inflammasomes. DMB reversed EMT-related marker expression in both in vivo and in vitro models. Notably, overexpression of NLRP3 in vitro partially abrogated the suppressive effect of DMB on the EMT.
DMB ameliorates pulmonary fibrosis by inhibiting NLRP3 inflammasome activation and suppressing the EMT. Inhibition of NLRP3 appears to play a critical role in mediating the antifibrotic effects of DMB. These findings imply that DMB may represent a promising therapeutic candidate for clinical management of IPF.
特发性肺纤维化（IPF）是一种以炎症和纤维化为特征的慢性进行性肺部疾病。去甲基小檗碱（DMB）是一种源自中药的天然化合物，具有抗炎和抗纤维化特性。本研究探讨了DMB在肺纤维化中的治疗潜力，并阐明其潜在的作用机制。
通过气管内注射博来霉素（BLM，1.5mg/kg）诱导雄性C57BL/6小鼠发生肺纤维化。将小鼠随机分为四组（每组n = 10）：对照组、BLM组、BLM + DMB（5mg/kg）组和BLM + DMB（10mg/kg）组。通过用转化生长因子-β1（TGF-β1，5ng/mL）刺激MLE-12细胞建立肺纤维化的体外模型。使用苏木精和伊红染色、肺功能测试和微型计算机断层扫描评估肺结构和功能变化。通过体外诱导NLRP3过表达进一步探讨DMB减轻肺纤维化过程中NLRP3与上皮-间质转化（EMT）之间的关系。
DMB治疗显著减轻了组织病理学改变，并减少了肺组织中的胶原沉积。它还抑制了经典和非经典NLRP3炎性小体的激活。DMB在体内和体外模型中均逆转了与EMT相关的标志物表达。值得注意的是，体外NLRP3过表达部分消除了DMB对EMT的抑制作用。
DMB通过抑制NLRP3炎性小体激活和抑制EMT来改善肺纤维化。NLRP3的抑制似乎在介导DMB的抗纤维化作用中起关键作用。这些发现表明，DMB可能是IPF临床治疗的一个有前景治疗候选药物。
