IκBβ-mediated NF-κB activation confers protection against hyperoxic lung injury.
Supplemental oxygen is frequently used in an attempt to improve oxygen delivery; however, prolonged exposure results in damage to the pulmonary endothelium and epithelium. Although NF-κB has been identified as a redox-responsive transcription factor, whether NF-κB activation exacerbates or attenuates hyperoxic lung injury is unclear. We determined that sustained NF-κB activity mediated by IκBβ attenuates lung injury and prevents mortality in adult mice exposed to greater than 95% O2. Adult wild-type mice demonstrated evidence of alveolar protein leak and 100% mortality by 6 days of hyperoxic exposure, and showed NF-κB nuclear translocation that terminated after 48 hours. Furthermore, these mice showed increased expression of NF-κB-regulated proinflammatory and proapoptotic cytokines. In contrast, mice overexpressing the NF-κB inhibitory protein, IκBβ (AKBI), demonstrated significant resistance to hyperoxic lung injury, with 50% surviving through 8 days of exposure. This was associated with NF-κB nuclear translocation that persisted through 96 hours of exposure. Although induction of NF-κB-regulated proinflammatory cytokines was not different between wild-type and AKBI mice, significant up-regulation of antiapoptotic proteins (BCL-2, BCL-XL) was found exclusively in AKBI mice. We conclude that sustained NF-κB activity mediated by IκBβ protects against hyperoxic lung injury through increased expression of antiapoptotic genes.
1 Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
Katherine A
KA
Michaelis
Fadeke
F
Agboke
Thanh
T
Liu
Kristie
K
Han
Manasa
M
Muthu
Csaba
C
Galambos
Guang
G
Yang
Phyllis A
PA
Dennery
Clyde J
CJ
Wright
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D018496:Hyperoxia / Q000235:genetics* / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D055370:Lung Injury / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
D016207:Cytokines; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B