Objective To explore the effect of macrolide antibiotics (erythromycin) on tumor necrosis factor (TNF)-α and interleukin (IL)-8 in hyperoxia-induced lung tissue of premature newborn rats, and to study the intervention effect of erythromycin on hyperoxia-induced lung injury. Methods One-day old preterm Sprague Dawley rats were randomly divided into four groups by random number table method: air+ sodium chloride group, air+ erythromycin group, hyperoxia+ sodium chloride group, hyperoxia+ erythromycin group. Hyperoxia groups were continuously exposed to oxygen (oxygen>0.85) and air group in room air. After 1, 7, 14 days of exposure, the preterm rats of four groups were sacrificed, whole lung of these rats were isolated, the lung histological changes were observed by hematoxylin-eosin staining, TNF-α and IL-8 in pulmonary tissue homogenate were detected by ELISA. Results The results showed that: (1) Compared with air+ sodium chloride group, TNF-α and IL-8 expression in hyperoxia+ sodium chloride group were significantly increased (P<0.05) after 1, 7 days of exposure[1 d: TNF-α: (16.163±0.574) ng/ml vs.(21.923±2.066) ng/ml, IL-8: (18.214±3.649) ng/ml vs.(23.546±5.240) ng/ml; 7 d: TNF-α: (15.940±0.821) ng/ml vs.(19.688±0.764) ng/ml, IL-8: (18.541±4.114) ng/ml vs.(24.255±4.692) ng/ml], in particular, TNF-α expression appeared to increase earlier, their expression became significantly weak in 14 days (P<0.05). (2) Compared with hyperoxia+ sodium chloride group, TNF-α and IL-8 expression in hyperoxia+ erythromycin group became significantly weak after 1, 7, 14 days of exposure (P<0.05) after the intervention of erythromycin[1 d: TNF-α: (21.923±2.066) ng/ml vs.(18.903±1.851) ng/ml, 7 d: IL-8: (24.255±4.692) ng/ml vs.(23.508±3.543) ng/ml, 14 d: TNF-α: (16.443±5.466) ng/ml vs.(14.453±0.963) ng/ml], but their expression became weaker in 14 days than that in 1, 7 days. Conclusion The release of inflammatory mediators TNF-α and IL-8 induced by oxidation outbreak participates in the development of hyperoxia induced lung injury, erythromycin may regulate immune function, inhibits the levels of oxidant-mediated TNF-α and IL-8 induced by oxidation outbreak, and alleviate hyperoxia lung injury in premature rats. Key words: Erythromycin; Hyperoxia; Lung injury; Tumor necrosis factor-α; Interleukin-8; Rat