Cilostazol mitigates amiodarone-induced pulmonary toxicity and fibrosis by regulating the cAMP/TGF-β1 pathway-mediated epithelial-to-mesenchymal transition in rats.

Cilostazol, a selective phosphodiesterase type III inhibitor, enhances intracellular cAMP and exhibits potent antioxidant and anti-inflammatory properties. This study aimed to investigate the protective effect of cilostazol (50 mg/kg/day, orally) against amiodarone (AMIO)-induced pulmonary fibrosis (PF) and to elucidate its underlying mechanisms. Lung index as well as total and differential cell counts in bronchoalveolar lavage fluid (BALF) were estimated. Histopathological changes were evaluated using hematoxylin and eosin (H&E) and Masson's trichrome staining. Malondialdehyde (MDA) and glutathione (GSH) contents were assessed colorimetrically, while TNF-α, IL-1β, and cAMP levels in the lungs were determined using ELISA. TGF-β1 and vimentin expressions were examined immunohistochemically, SIRT1 protein expression by Western blotting, and EPAC1 gene expression by RT-PCR. AMIO administration caused significant increases in lung index, inflammatory cytokines, oxidative stress markers, and fibrotic mediators, accompanied by a decline in GSH and cAMP levels and severe histopathological damage. Cilostazol co-treatment markedly attenuated these alterations, decreasing TNF-α, IL-1β, MDA, TGF-β1, and vimentin while restoring GSH, cAMP, SIRT1, and EPAC1 expressions and improving lung architecture. Cilostazol mitigates AMIO-induced PF through attenuation of oxidative stress, inflammation, and EMT, potentially via activation of the SIRT1/EPAC1/cAMP pathway. These findings highlight cilostazol as a promising therapeutic adjunct against drug-induced PF.