Paeoniflorin (PF) is a monoterpene glucoside and the main component of the total glycosides of paeony (TGP) extracted from the roots of Paeonia lactiflora which is commonly used in Traditional Chinese Medicine for centuries.More in-depth studies have reported that paeoniflorin might have an effect on the oxidative stress;however,the mechanism is still unknown.Even the relationship between the duration of effect and time remains unclear.In present study,the model of COPD was created in Sprague-Dawley(SD) rats by being exposed to tobacco smoke of 20 cigarettes for 1 hour/day,6 days/week,for either 12 weeks,24 weeks,or 36 weeks.Data from pulmonary function demonstrated rats were suffering from a continuous decline in lung function parameters which are characterized for development of COPD.Moreover,these changes come along with the histological analysis of lung tissue which presented that infiltrated inflammatory cells were significantly increased in the model group compared with NC group.Elisa result also suggested that CS induced oxidative stress in the COPD model group.Fortunately,paeoniflorin treatment can decrease the level of oxidative stress and resulted in significant ATF4 and Nrf2 expressions which are the main cause of increased level of antioxidant enzymes.All these findings together suggested that smoke inhalation can pull off the trigger of oxidative stress from the very beginning.The duration of 24-weeks treatment of paeoniflorin especially in the dosage of 40mg/kg*d worked out a better outcome at the end of the experiment partially throughout quenching ROS and up regulating antioxidant enzymes via an Nrf2-dependent mechanism.