〔Abstract〕 Objective To investigate the protective effect of caffeine on oxidative stress injury induced by hyperoxia in neonatal SD rats with bronchopulmonary dysplasia(BPD) and its related mechanism.Methods Neonatal SD rats were randomly divided into air control group(N group),caffeine air control group(NC group),model group(H group) and caffeine intervention group(HC group).The high oxygen induction method was used to establish the BPD model.Blood and lung tissue of six samples were collected from each group on day 3,7,14 and 21.Each group was divided into four subgroups according to four days of age.The 21-day panel of four groups measured their body weights.The upper lobe of the right lung was used to measure wet-dry weight ratio(W/D) of lung tissue in each group; the lower lobe of the right lung was sliced after paraffin embedding and stained with hematoxylin-eosin(HE) to observe morphological changes and calculate radial alveolar count(RAC) values; the levels of malondialdehyde(MDA) and superoxide dismutase(SOD) in blood and lung tissues were determined to evaluate the imbalance of oxidative and antioxidant homeostasis in neonatal rats; real-time fluorescence quantitative reverse transcription polymerase chain reaction(RT-qPCR) was used to detect the relative expression level of nuclear factor-erythroid 2-related factor 2(Nrf2) mRNA in lung tissues.Results(1) H group showed a gradual decline in activity after 3 days and an increasing trend in body weight after 14 days.(2) W/D value of H group reached its peak at day 14,and the trend of HC group was similar to that of H group.(3) The lung tissue structure of H group was irregular,RAC value of which decreased significantly after 7 days of peak,and the difference between H group and HC group was statistically significant( P<0. 01).(4) The MDA value of H group increased on day 7 and gradually decreased on day 14,while the SOD activity decreased obviously on day 7,and there were significant differences in MDA and SOD activity between H group and HC group at 14 days and 21 days( P<0. 05).(5) The expression of Nrf2 mRNA in H group was significantly enhanced at day 7 and stabilized at day 14,and there were statistically significant differences between H and HC groups at day 3,day 7 and day 14( P<0. 05).(6) The relative expression level of Nrf2 mRNA was positively correlated with MDA and negatively correlated with SOD. Conclusion Caffeine can regulate oxidative stress response through Nrf2 pathway and alleviate lung oxidative stress injury induced by hyperoxia in neonatal rats with BPD.