Inactivation of I kappaB-kinase-beta dependent genes in airway epithelium reduces tobacco smoke induced acute airway inflammation.

We have examined the role of NF-kappaB regulated genes in airway epithelium in mediating tobacco smoke induced airway inflammation in studies of CC10-Cre(tg)/Ikk beta(Delta/Delta) mice in which NF-kappaB signaling through I kappaB-kinase-beta (IKK-beta) is selectively ablated in epithelial cells in the airway. CC10-Cre(tg)/Ikk beta(Delta/Delta) mice exposed to tobacco smoke for seven days had a significant decrease in the number of BAL cells (total cells, neutrophils, and macrophages) as well as significantly reduced numbers of peribronchial cells (F4/80+ and myeloperoxidase+) compared to tobacco exposed WT mice. In addition to the reduction in peribronchial cells, CC10-Cre(tg)/Ikk beta(Delta/Delta) mice exposed to tobacco smoke had a significant decrease in the number of macrophages and neutrophils in the alveolar space suggesting that inactivation of NF-kappaB in the airway epithelium influenced the number of neutrophils and macrophages recruited to the alveolus. Levels of the NF-kappaB regulated chemokines KC and MCP-1 were significantly reduced in lungs of tobacco smoke exposed CC10-Cre(tg)/Ikk beta(Delta/Delta) mice compared to tobacco exposed WT mice. In contrast, there was no significant difference in levels of NF-kappaB regulated MIP-1 alpha between CC10-Cre(tg)/Ikk beta(Delta/Delta) and WT mice. Lung sections of tobacco smoke exposed CC10-Cre(tg)/Ikk beta(Delta/Delta) mice immunostained with KC or MCP-1 antibodies demonstrated reduced expression of these chemokines in the airway epithelium, but not in alveolar epithelium. Overall, these studies demonstrate an important role for NF-kappaB regulated genes in airway epithelium in contributing to acute tobacco smoke induced airway inflammation not only in the peribronchial space but also in the alveolar space. (c) 2010 Elsevier B.V. All rights reserved.