Distinct functions of airway epithelial nuclear factor-kappaB activity regulate nitrogen dioxide-induced acute lung injury.
Reactive oxidants such as nitrogen dioxide (NO(2)) injure the pulmonary epithelium, causing airway damage and inflammation. We previously demonstrated that nuclear factor-κ B (NF-κB) activation within airway epithelial cells occurs in response to NO(2) inhalation, and is critical for lipopolysaccharide-induced or antigen-induced inflammatory responses. Here, we investigated whether manipulation of NF-κB activity in lung epithelium affected severe lung injuries induced by NO(2) inhalation. Wild-type C57BL/6J, CC10-IκBα(SR) transgenic mice with repressed airway epithelial NF-κB function, or transgenic mice expressing a doxycycline-inducible, constitutively active I κ B kinase β (CC10-rTet-(CA)IKKβ) with augmented NF-κB function in airway epithelium, were exposed to toxic levels of 25 ppm or 50 ppm NO(2) for 6 hours a day for 1 or 3 days. In wild-type mice, NO(2) caused the activation of NF-κB in airway epithelium after 6 hours, and after 3 days resulted in severe acute lung injury, characterized by neutrophilia, peribronchiolar lesions, and increased protein, lactate dehydrogenase, and inflammatory cytokines. Compared with wild-type mice, neutrophilic inflammation and elastase activity, lung injury, and several proinflammatory cytokines were significantly suppressed in CC10-IκBα(SR) mice exposed to 25 or 50 ppm NO(2). Paradoxically, CC10-rTet-(CA)IKKβ mice that received doxycycline showed no further increase in NO(2)-induced lung injury compared with wild-type mice exposed to NO(2), instead displaying significant reductions in histologic parameters of lung injury, despite elevations in several proinflammatory cytokines. These intriguing findings demonstrate distinct functions of airway epithelial NF-κB activities in oxidant-induced severe acute lung injury, and suggest that although airway epithelial NF-κB activities modulate NO(2)-induced pulmonary inflammation, additional NF-κB-regulated functions confer partial protection from lung injury.
Ather
Jennifer L
JL
Department of Pathology, University of Vermont, Burlington, VT 05405, USA.
Alcorn
John F
JF
Brown
Amy L
AL
Guala
Amy S
AS
Suratt
Benjamin T
BT
Janssen-Heininger
Yvonne M W
YM
Poynter
Matthew E
ME
D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002467:Cell Nucleus / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D009585:Nitrogen Dioxide; D011014:Pneumonia / Q000378:metabolism; D021381:Protein Transport; D051996:Transcription Factor RelA / Q000378:metabolism; D014598:Uteroglobin / Q000378:metabolism
D018925:Chemokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C556390:Scgb1a1 protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D014598:Uteroglobin; D007770:L-Lactate Dehydrogenase; D009585:Nitrogen Dioxide