Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th of October, Egypt.
Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th of October, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Mar;392(3):279-286. doi: 10.1007/s00210-018-1586-1. Epub 2018 Nov 24.
Amitriptyline is a tricyclic antidepressant that was suggested to have antifibrotic potential. The current study aimed to investigate the modulatory effects of amitriptyline on bleomycin-induced pulmonary fibrosis in rats. Rats were randomly assigned into 4 groups: normal control, bleomycin control, amitriptyline+bleomycin, and amitriptyline only treated group. Lung injury was evaluated through the histological examination and immunohistochemical detection of α-smooth muscle actin (α-SMA) in lung tissue, in addition to the biochemical assessment of pulmonary contents of hydroxyproline and transforming growth factor beta-1 (TGF-β1). In addition, the following parameters were investigated for studying the possible mechanisms of amitriptyline antifibrotic effect: inducible nitric oxide synthase (iNOS), nuclear factor-κβ (NF-κβ), tumor necrosis factor-alpha (TNF-α), serpine-1, p53, nuclear factor erythroid 2-related factor 2 (Nrf2), lipid peroxides, and reduced glutathione (GSH). Amitriptyline exhibited potent antifibrotic effect that was reflected upon the histopathological examination and through its ability to suppress all the fibrotic parameters. Amitriptyline successfully suppressed the expression of NF-κβ, Nrf2, iNOS, and p53 in lung tissues besides the inhibition of other oxidative stress and inflammatory mediators. Amitriptyline could be a promising treatment to pulmonary fibrosis. Amitriptyline not only prevents the depression and its drawbacks in patients suffering from pulmonary fibrosis but also it can suppress fibrosis through variable mechanisms mainly via inhibition of NF-κβ/TNF-α/TGF-β pathway in addition to inhibition of Nrf2 and iNOS expression.
阿米替林是一种三环类抗抑郁药，具有抗纤维化作用。本研究旨在探讨阿米替林对博来霉素诱导的大鼠肺纤维化的调节作用。大鼠随机分为 4 组：正常对照组、博来霉素对照组、阿米替林+博来霉素组和阿米替林单独治疗组。通过肺组织α-平滑肌肌动蛋白（α-SMA）的组织学检查和免疫组织化学检测，以及羟脯氨酸和转化生长因子β-1（TGF-β1）的肺组织生化评估，评价肺损伤。此外，还研究了阿米替林抗纤维化作用的可能机制的以下参数：诱导型一氧化氮合酶（iNOS）、核因子-κβ（NF-κβ）、肿瘤坏死因子-α（TNF-α）、丝氨酸蛋白酶抑制剂 1（serpine-1）、p53、核因子红细胞 2 相关因子 2（Nrf2）、脂质过氧化物和还原型谷胱甘肽（GSH）。阿米替林表现出强大的抗纤维化作用，这反映在组织病理学检查中，并通过其抑制所有纤维化参数的能力。阿米替林成功抑制了 NF-κβ、Nrf2、iNOS 和 p53 在肺组织中的表达，同时抑制了其他氧化应激和炎症介质。阿米替林可能是治疗肺纤维化的一种有前途的方法。阿米替林不仅可以预防患有肺纤维化的患者的抑郁及其缺点，而且可以通过多种机制抑制纤维化，主要通过抑制 NF-κβ/TNF-α/TGF-β 途径，以及抑制 Nrf2 和 iNOS 的表达。
