| First Author | Ather JL | Year | 2010 |
| Journal | Am J Respir Cell Mol Biol | Volume | 43 |
| Issue | 4 | Pages | 443-51 |
| PubMed ID | 19901348 | Mgi Jnum | J:177813 |
| Mgi Id | MGI:5296303 | Doi | 10.1165/rcmb.2008-0416OC |
| Citation | Ather JL, et al. (2010) Distinct functions of airway epithelial nuclear factor-kappaB activity regulate nitrogen dioxide-induced acute lung injury. Am J Respir Cell Mol Biol 43(4):443-51 |
| abstractText | Reactive oxidants such as nitrogen dioxide (NO(2)) injure the pulmonary epithelium, causing airway damage and inflammation. We previously demonstrated that nuclear factor-kappa B (NF-kappaB) 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-kappaB activity in lung epithelium affected severe lung injuries induced by NO(2) inhalation. Wild-type C57BL/6J, CC10-IkappaBalpha(SR) transgenic mice with repressed airway epithelial NF-kappaB function, or transgenic mice expressing a doxycycline-inducible, constitutively active I kappa B kinase beta (CC10-rTet-(CA)IKKbeta) with augmented NF-kappaB 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-kappaB 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-IkappaBalpha(SR) mice exposed to 25 or 50 ppm NO(2). Paradoxically, CC10-rTet-(CA)IKKbeta 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-kappaB activities in oxidant-induced severe acute lung injury, and suggest that although airway epithelial NF-kappaB activities modulate NO(2)-induced pulmonary inflammation, additional NF-kappaB-regulated functions confer partial protection from lung injury. |
