Interleukin-6–Induced Protection in Hyperoxic Acute Lung Injury

Abstract

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.

Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells☆

“…The levels of IL-6 and IL-11 are significantly correlated with the protection of animals from hyperoxic cell death and acute lung injury [90,91]. Transgenic mice that over-express either IL-6 or IL-11 exhibited remarkable tolerance and survival advantages following exposure to hyperoxia compared to the wildtype mice [90][91][92].…”

The Role of Angiopoietin 2 in Hyperoxia-Inuduced Acute Lung Injury

“…[35][36][37][38] It is possible that both cell death pathways co-exist or that another distinct mechanism may be induced in hyperoxia. 27,39,40 The dose and/or duration of hyperoxia exposure can cause different cell types in the lung to undergo death via distinct or overlapping mechanisms.…”

“…27,39,40 The dose and/or duration of hyperoxia exposure can cause different cell types in the lung to undergo death via distinct or overlapping mechanisms. Recent studies from our laboratory and others have added to this pathogenic paradigm by demonstrating that ROS mediate their effects, in part, by inducing an endothelial and epithelial cell death response with features of apoptosis and necrosis 6,20,21,25,36,41,42 and that a variety of exogenously administered regulators inhibit these toxic events by regulating local cell death responses. 5,6,20 In addition, although structural cell apoptosis (such as that seen in HALI) can stimulate tissue inflammation, 43,44 hyperoxia-induced inflammation cannot be attributed solely to the nearby cell death response.…”

“…59 Hyperoxia causes a pulmonary endothelial and epithelial cell death response with features compatible with apoptosis including chromatin condensation and DNA fragmentation. 6,36,41,64,65 However, microscopy has demonstrated that these lesions evolve into frank necrosis with continued hyperoxic exposure. 42 In accord with the known context-dependent effector profile of Ang2, 51,63 we noted that Ang2 induced epithelial cell necrosis in hyperoxia, but not under normoxic states.…”

Effect of Short-term Exposure of Different Concentrations of Hyperoxia on Fetal Alveolar Type II Cell Death

“…However, hyperoxia can generate lung injury [3][4][5][6][7] , which is known well as a major contributing factor to the development of BPD. Importantly, hyperoxia has a main biological effect of cell death 8) .…”