Amitriptyline attenuates bleomycin-induced pulmonary fibrosis: modulation of the expression of NF-κβ, iNOS, and Nrf2

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Date

2019

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Article

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Springer Verlag

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Naunyn-Schmiedeberg's Archives of Pharmacology
392

Abstract

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 ?-smooth muscle actin (?-SMA) in lung tissue, in addition to the biochemical assessment of pulmonary contents of hydroxyproline and transforming growth factor beta-1 (TGF-?1). In addition, the following parameters were investigated for studying the possible mechanisms of amitriptyline antifibrotic effect: inducible nitric oxide synthase (iNOS), nuclear factor-?? (NF-??), tumor necrosis factor-alpha (TNF-?), 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-??, 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-??/TNF-?/TGF-? pathway in addition to inhibition of Nrf2 and iNOS expression. � 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

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Keywords

Amitriptyline, iNOS, Nrf2, Nuclear factor-??, Pulmonary fibrosis, alpha smooth muscle actin, amitriptyline, collagen, glutathione, hydroxyproline, immunoglobulin enhancer binding protein, inducible nitric oxide synthase, lipid peroxide, protein p53, transcription factor Nrf2, transforming growth factor beta1, amitriptyline, bleomycin, immunoglobulin enhancer binding protein, inducible nitric oxide synthase, Nfe2l2 protein, rat, Nos2 protein, rat, transcription factor Nrf2, animal experiment, animal model, animal tissue, antifibrotic activity, Article, bleomycin-induced pulmonary fibrosis, cell infiltration, controlled study, inflammatory cell, lung parenchyma, male, nonhuman, protein expression, rat, animal, drug effect, lung, lung fibrosis, metabolism, pathology, Wistar rat, Amitriptyline, Animals, Bleomycin, Lung, Male, NF-E2-Related Factor 2, NF-kappa B, Nitric Oxide Synthase Type II, Pulmonary Fibrosis, Rats, Wistar

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