Abstract: Objective　To explore hypodermic injection of prostaglandin E1 (PGE-1) for the treatment of hyperoxic lung injury and mechanism in neonatal rats. Method　A total of 45 newborn Wistar rats were randomly divided into control group, hyperoxic lung injury model group and hyperoxic lung injury + PGE-1 group 15 rats each. The rats in hyperoxia lung injury model group and hyperoxia lung injury group + PDE1 were exposed to >85% concentration of oxygen in the experimental cabin, and the control group was placed in the air under the same pressure. In control group and hyperoxia lung injury model group, 0.9% sodium chloride was injected subcutaneously from first day after birth, and hyperoxia lung injury + PGE-1 group was injected with PGE-1 at 2 μg/(kg·d) for 7 days. The lung dry/wet weight ratio was calculated and the total number of leukocytes in bronchoalveolar lavage fluid (BALF) was counted. The morphological changes of bronchi and alveoli were observed by HE staining. The apoptosis of lung tissue was observed by nuclear staining and TUNEL, and the expression of GRP78 and CHOP protein in lung tissue was detected by Western blotting. Results　There were significant differences in lung dry/wet weight ratio, BALF leukocyte count, apoptosis index, GRP78 and CHOP protein expression among control group, hyperoxia lung injury model group and hyperoxia lung injury group + PGE-1 (P<0.001). In the hyperoxic lung injury model group, the indexes mentioned above were the highest, followed by hyperoxic lung injury + PGE-1 group and control group, and there were significant differences between groups (P<0.05). The lung tissue pathological observation in hyperoxia lung injury model group showed the alveolar enlargement and fusion, interstitial cell edema, and fibrous exudation. The degree in pathological changes in hyperoxia lung injury group + PGE-1 were in the middle of the hyperoxic lung injury model group and control group. Conclusion　Subcutaneous injection of PGE-1 has a therapeutic effect on hyperoxic lung injury in neonatal rats. The mechanism may be related to the inhibition of the expression of CHOP and GRP78 protein.