Mohammadi Hamaneh Amirabbas, Nejati Fatemeh, Teymoori Masuleh Mohammad, Manavi Mohammad Amin, Kazemzadeh Houman, Shafaroodi Hamed, Tavangar Seyed Mohammad, Dehpour Ahmad Reza
Experimental Medicine Research Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Experimental Medicine Research Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
Int Immunopharmacol. 2025 Sep 23;162:115182. doi: 10.1016/j.intimp.2025.115182. Epub 2025 Jul 10.
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by excessive extracellular matrix (ECM) accumulation, fibroblast activation, and chronic inflammation. This study examined the antifibrotic effects of naltrexone (NTX), an opioid receptor antagonist, in a bleomycin (BLM)-induced pulmonary fibrosis model in Wistar rats. Daily administration of NTX significantly reduced alveolar wall thickening, collagen deposition, and histopathological injury scores. At higher doses, NTX markedly decreased levels of pro-inflammatory cytokines (TNF-α, IL-6, TGF-β), oxidative stress markers (MPO, NO), and key fibrotic markers including α-SMA and delta opioid receptor (DOR). Additionally, NTX restored antioxidant defenses (GSH, TAC) and enhanced GSK-3β phosphorylation, thereby modulating the Wnt/β-catenin and NF-κB signaling pathways. To further investigate the cellular mechanisms underlying NTX's antifibrotic activity, in vitro experiments were conducted using BLM-stimulated NIH-3 T3 fibroblasts. NTX inhibited the production of collagen type I and III, tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and matrix metalloproteinases (MMP-2 and MMP-9) in a dose- and time-dependent manner. This dual regulation of ECM synthesis and degradation suggests a more balanced therapeutic strategy compared to merely inhibiting collagen accumulation. Molecular docking analyses revealed strong interactions between NTX and key proteins involved in inflammatory and fibrotic signaling cascades. Notably, NTX at a dose of 20 mg/kg demonstrated antifibrotic efficacy comparable to that of pirfenidone. Collectively, these findings suggest that NTX exerts protective effects in pulmonary fibrosis by simultaneously targeting inflammation, oxidative stress, and ECM remodeling. Given its favorable tolerability and potential cost-effectiveness, NTX emerges as a promising candidate for IPF therapy. Further clinical investigations are warranted to evaluate its translational potential.
特发性肺纤维化（IPF）是一种进行性致命性肺部疾病，其特征为细胞外基质（ECM）过度积聚、成纤维细胞活化和慢性炎症。本研究在博来霉素（BLM）诱导的Wistar大鼠肺纤维化模型中，检测了阿片受体拮抗剂纳曲酮（NTX）的抗纤维化作用。每日给予NTX可显著减轻肺泡壁增厚、胶原沉积和组织病理学损伤评分。在较高剂量下，NTX可显著降低促炎细胞因子（TNF-α、IL-6、TGF-β）、氧化应激标志物（MPO、NO）以及包括α-SMA和δ阿片受体（DOR）在内的关键纤维化标志物的水平。此外，NTX恢复了抗氧化防御功能（GSH、TAC）并增强了GSK-3β磷酸化，从而调节Wnt/β-连环蛋白和NF-κB信号通路。为进一步研究NTX抗纤维化活性的细胞机制，使用BLM刺激的NIH-3 T3成纤维细胞进行了体外实验。NTX以剂量和时间依赖性方式抑制I型和III型胶原、金属蛋白酶组织抑制剂（TIMP-1和TIMP-2）以及基质金属蛋白酶（MMP-2和MMP-9）的产生。与单纯抑制胶原积累相比，这种对ECM合成和降解的双重调节提示了一种更为平衡的治疗策略。分子对接分析揭示了NTX与参与炎症和纤维化信号级联反应的关键蛋白之间存在强相互作用。值得注意的是，20 mg/kg剂量的NTX显示出与吡非尼酮相当的抗纤维化疗效。总体而言，这些发现表明NTX通过同时靶向炎症、氧化应激和ECM重塑，在肺纤维化中发挥保护作用。鉴于其良好的耐受性和潜在的成本效益，NTX有望成为IPF治疗的候选药物。有必要进行进一步的临床研究以评估其转化潜力。
