In the present study, intratracheal instillation of BLM resulted in down-regulated Smad3 mRNA expression and interestingly, this expression was significantly up-regulated by hesperidin which might have, in turn, created a negative feedback loop that down-regulated TGF-β signaling and collagen-I mRNA expression to ameliorate BLM-induced IPF. The gene discussed is SMAD3; the disease is idiopathic pulmonary fibrosis.