Zaafan M.A.Haridy A.R.Abdelhamid A.M.Pharmacology and Toxicology DepartmentFaculty of PharmacyOctober University for Modern Sciences and Arts (MSA)6th of OctoberEgypt; Biochemistry DepartmentFaculty of PharmacyOctober University for Modern Sciences and Arts (MSA)6th of OctoberEgypt2020-01-092020-01-092019281298https://doi.org/10.1007/s00210-018-1586-1PubMed ID 30474696https://t.ly/zNMEXScopusAmitriptyline 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.EnglishAmitriptylineiNOSNrf2Nuclear factor-??Pulmonary fibrosisalpha smooth muscle actinamitriptylinecollagenglutathionehydroxyprolineimmunoglobulin enhancer binding proteininducible nitric oxide synthaselipid peroxideprotein p53transcription factor Nrf2transforming growth factor beta1amitriptylinebleomycinimmunoglobulin enhancer binding proteininducible nitric oxide synthaseNfe2l2 protein, ratNos2 protein, rattranscription factor Nrf2animal experimentanimal modelanimal tissueantifibrotic activityArticlebleomycin-induced pulmonary fibrosiscell infiltrationcontrolled studyinflammatory celllung parenchymamalenonhumanprotein expressionratanimaldrug effectlunglung fibrosismetabolismpathologyWistar ratAmitriptylineAnimalsBleomycinLungMaleNF-E2-Related Factor 2NF-kappa BNitric Oxide Synthase Type IIPulmonary FibrosisRats, WistarArticlehttps://doi.org/10.1007/s00210-018-1586-1PubMed ID 30474696