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.