Neonatal animals of several species are more tolerant of hyperoxic exposure than are adults. However, the mechanisms of increased neonatal tolerance are unknown, as are the cell types that contribute to oxygen resistance. This study examined hyperoxic lung injury in neonatal and adult C57BL/6 mice. Adults and neonatal mice were exposed to > 95% oxygen for 78 h and 10 days, respectively. Lung mRNAs were assayed by RNase protection assay. After 72 h of exposure, the messages encoding tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta and 6 (IL-1 beta, IL-6) were increased 2-fold in adult lungs. However, at this time point these mice are near or at lethality. No alterations in neonatal lung mRNAs were detected until 7 days of oxygen exposure. At that time neonatal mice demonstrated increases in lung mRNAs encoding TNF-alpha, IL-1 beta, and IL-6 of 3-, 5-, and 8-fold, respectively. Acute alveolitis and slight edema were detected, but lethality wasn't observed until 10 days of exposure. In situ hybridization in neonatal mice suggests accumulation of TNF-alpha and IL-1 beta transcripts in pulmonary interstitial macrophages and in a subset of neutrophils after 7 days of exposure. Messages encoding IL-1 alpha, IL-2, IL-3, IL-4, IL-5,IL-10 interferon-gamma (IFN-gamma), and TNF-beta were not altered from controls in either adult or neonatal mice at any time point examined. In conclusion, adult mice demonstrate little change in cytokine mRNA until lethality is imminent, whereas newborn mice demonstrate an acute induction of TNF-alpha, IL-1 beta, and IL-6 early in the development of hyperoxic injury, which suggests that a rapid cytokine response early in the development of hyperoxic injury may play an important role in the adaptation of neonatal lungs to toxicity from prolonged oxygen exposure.