Although considerable evidence suggests that bronchopulmonary dysplasia (BPD) is the result of prolonged inflammation and impaired healing of the immature lung, the mediators that regulate inflammation in neonatal lung injury have not been completely elucidated. We examined whether the cytokines IL-6 and tumor necrosis factor-a (TNF) interact to modulate a cascade of cell-cell signaling events involved in inflammation contributing to the development of BPD. To determine the relative activities of these cytokines in neonatal lung injury, lung lavage samples were serially obtained from 1 to 28 d from 11 infants with self-limited respiratory distress syndrome (RDS), 19 infants with evolving BPD, and 10 control infants ventilated for nonpulmonary reasons. On the first day of life, there were no differences in antigenic IL-6 concentrations in lavage fluids among the BPD, RDS, and control groups, but IL-6 activity determined by the 7TD1 proliferation assay was 15-fold and 6.6-fold higher in lung lavage of infants who developed BPD compared with activities in lavage from control and RDS infants, respectively (control, Exogenous surfactant therapy has dramatically improved survival of very-low-birth-weight infants with RDS, but it has not affected the incidence of the neonatal chronic lung disorder B P D (1). This suggests that factors in addition t o surfactant deficiency contribute t o neonatal lung injury. Pathologic findings in B P D are consistent with a process of prolonged lung inflammation and impaired healing (2, 3). In human infants with RDS (4-6) 49.4 ? 17.6; RDS, 117.3 2 59.6; BPD, 779.5 2 212.6 x 10' hybridoma units/L, mean * SEM,p = 0.02). This suggests that pathways for inactivating or inhibiting IL-6 that may be present in the lungs of RDS and control infants may be deficient in BPD infants. IL-6 activity remained elevated in lavage of BPD infants for the first 2 wk and declined to low levels by d 28. There were no differences among groups on the first day of life for TNF antigen concentration or TNF activity determined by the L929 bioassay. Detectable but low TNF activity was found in BPD samples, with peak activity found in d-14 samples. Differences in complex interactions among these and other cytokines with their receptors and inhibitors may predispose some infants with RDS to develop BPD. (Pediuh. Res 36: 244-252, 1994) Abbreviations RDS, respiratory distress syndrome BPD, bronchopulmonary dysplasia TNF, tumor necrosis factor-a PROM, prolonged rupture of membranes and in primate models of acute lung injury (7), there is a rapid influx of neutrophils into the lung during the first 48 t o 96 h after initial injury followed b y a n increase in alveolar macrophages with subsequent resolution of airw a y inflammation. In contrast, in infants w h o develop BPD, the neutrophil influx is prolonged and the alveolar macrophage entry is delayed and blunted (5). nolysis (13), the mediators that regulate neonatal lung