title: Inactivation of I kappaB-kinase-beta dependent genes in airway epithelium reduces tobacco smoke induced acute airway inflammation.
abstract: 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.
authors.affiliation: Department of Medicine, University of California San Diego, San Diego, California 92093-0635, USA. pulsy@korea.ac.kr
authors.forename: Sang Yeub
authors.initials: SY
authors.lastname: Lee
authors.forename: Marina
authors.initials: M
authors.lastname: Miller
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Dae Jin
authors.initials: DJ
authors.lastname: Song
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D012907:Smoking / Q000009:adverse effects*
chemical_list: D018925:Chemokines; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B