Evaluation of the Antifibrotic Effect of Serotonin Receptor Antagonists on Bleomycin Induced Pulmonary Fibrosis in Rats

Idiopathic pulmonary fibrosis (IPF) is believed to be an epithelial-fibroblast disease. Activated epithelial cells are thought to release potent fibrogenic molecules and cytokines, such as tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta1 (TGF-β1), which in turn foster the transformation of fibroblasts into myofibroblasts and promote production of extracellular matrix molecules and so collagen deposition. Serotonin (5-hydroxy tryptamine, 5-HT) is an important mediator for lung fibrogenesis, with implication of 5-HT2A/B/C receptors. However, the antifibrotic effects of all 5-HT2 receptor subtypes versus 5-HT2A/C blockade is needing to be explored. So, the present study was conducted to evaluate the antifibrotic effects of mirtazapine (5-HT2A/C receptor blocker) and cyproheptadine (5-HT2A/B/C receptor blocker) on body weight changes, survival rates, the lung hydroxyproline and TGF-β1 levels as well as the histopathological changes of lung fibrosis, in bleomycin-induced rat pulmonary fibrosis. Eighty-eight adult rats were used and subdivided randomly into 11 groups. One normal control, five vehicle control groups and five groups with IPF that induced by intra-tracheal instillation of bleomycin alone (5mg/kg), or bleomycin and treated with either mirtazapine (15 mg/kg/day) or cyproheptadine (5 mg/kg/day) for 7 and 14 days. Oral treatment with either mirtazapine or cyproheptadine, significantly ameliorated losses in body weights, reduction in survival rates, lung hydroxyproline and TGF-β1 levels and the inflammatory effects in lungs induced by bleomycin. The mechanisms underlying these therapeutic effects could be dependent on the reduction of TGF-β1 actions as decreasing lung inflammation and production and deposition of collagen in fibrotic lung tissues.