Interleukin-6-induced protection in hyperoxic acute lung injury

Hyperoxic lung injury is commonly encountered in patients who require treat ment with high concentrations of inspired oxygen. To determine whether inte rleukin (IL)-6 is protective in oxygen toxicity, we compared the effects of 100% O-2 in transgenic: mice that overexpress IL-6 in the lung and transge ne (-) controls. IL-6 markedly enhanced survival, with 100% of transgene (- ) animals dying within 72 to 96 h, 100% of transgene (+) animals living for more than 8 d and more than 90% of transgene (+) animals living longer tha n 12 d. This protection was associated with markedly diminished alveolar-ca pillary protein leak, endothelial and epithelial membrane injury, and lung lipid peroxidation. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-6 markedly diminished this cy topathic response. The protective effects of IL-6 were not associated with significant alterations in the activities of copper/zinc superoxide dismuta se (SOD) or manganese SOD. They were, however, associated with the enhanced accumulation of the cell-death inhibitor Bcl-2 but not the cell-death stim ulator BAX, and with the heightened accumulation of the cell-death regulato r tissue inhibitor of metalloproteinase-l (TIMP-1). These studies demonstra te that IL-6 markedly diminishes hyperoxic lung injury and that this protec tion is associated with a marked diminution in hyperoxia-induced cell death and DNA fragmentation. They also demonstrate that this protection is not a ssociated with significant alterations in SOD activity, but is associated w ith the induction of Bcl-2 and TIMP-1.