Interleukin-6-induced protection in hyperoxic acute lung injury.
Hyperoxic lung injury is commonly encountered in patients who require treatment with high concentrations of inspired oxygen. To determine whether interleukin (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 transgene (-) 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 than 12 d. This protection was associated with markedly diminished alveolar-capillary 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 cytopathic response. The protective effects of IL-6 were not associated with significant alterations in the activities of copper/ zinc superoxide dismutase (SOD) or manganese SOD. They were, however, associated with the enhanced accumulation of the cell-death inhibitor Bcl-2, but not the cell-death stimulator BAX, and with the heightened accumulation of the cell-death regulator tissue inhibitor of metalloproteinase-1 (TIMP-1). These studies demonstrate that IL-6 markedly diminishes hyperoxic lung injury and that this protection is associated with a marked diminution in hyperoxia-induced cell death and DNA fragmentation. They also demonstrate that this protection is not associated with significant alterations in SOD activity, but is associated with the induction of Bcl-2 and TIMP-1.
Ward
N S
NS
Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and Yale University School of Medicine, Department of Pathology, New Haven, Connecticut 06520-8057, USA.
Waxman
A B
AB
Homer
R J
RJ
Mantell
L L
LL
Einarsson
O
O
Du
Y
Y
Elias
J A
JA
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D018496:Hyperoxia / Q000235:genetics* / Q000401:mortality; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000235:genetics* / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000235:genetics; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D000975:Antioxidants; C494827:Bax protein, mouse; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019715:Tissue Inhibitor of Metalloproteinase-1; D051028:bcl-2-Associated X Protein; D013482:Superoxide Dismutase