TARGETED LUNG EXPRESSION OF INTERLEUKIN-11 ENHANCES MURINE TOLERANCE OF 100-PERCENT OXYGEN AND DIMINISHES HYPEROXIA-INDUCED DNA FRAGMENTATION

Acute lung injury is a frequent and treatment-limiting consequence of therapy with hyperoxic gas mixtures. To determine if IL-11 is protecti ve in oxygen toxicity, we compared the effects of 100% O-2 on transgen ic mice that overexpress IL-11 in the lung and transgene (-) controls. IL-11 markedly enhanced survival in 100% O-2 with 100% of transgene ( -) animals dying within 72-96 h and > 90% of transgene (+) animals sur viving for more than 10 d. This protection was associated with markedl y diminished alveolar-capillary protein leak, endothelial and epitheli al membrane injury, lipid peroxidation, and pulmonary neutrophil recru itment. Significant differences in copper zinc superoxide dismutase an d catalase activities were not noted and the levels of total, reduced and oxidized glutathione were similar in transgene (+) and (-) animals . Glutathione reductase, glutathione peroxidase, and manganese superox ide dismutase activities were slightly higher in transgene (+) as vers us (-) mice after 100% O-2 exposure, and IL-11 diminished hyperoxia-in duced expression of IL-1 and TNF. Hyperoxia also caused cell death wit h DNA fragmentation in the lungs of transgene (-) animals and IL-11 ma rkedly diminished this cell death response. These studies demonstrate that IL-11 markedly diminishes hyperoxic lung injury. They also demons trate this protection is associated with small changes in lung antioxi dants, diminished hyperoxia-induced IL-1 and TNF production, and marke dly suppressed hyperoxia-induced DNA fragmentation.