Epithelial NF-κB orchestrates house dust mite-induced airway inflammation, hyperresponsiveness, and fibrotic remodeling.
NF-κB activation within the epithelium has been implicated in the pathogenesis of asthma, yet the exact role of epithelial NF-κB in allergen-induced inflammation and airway remodeling remains unclear. In the current study, we used an intranasal house dust mite (HDM) extract exposure regimen time course in BALB/c mice to evaluate inflammation, NF-κB activation, airway hyperresponsiveness (AHR), and airway remodeling. We used CC10-IκBαSR transgenic mice to evaluate the functional importance of epithelial NF-κB in response to HDM. After a single exposure of HDM, mRNA expression of proinflammatory mediators was significantly elevated in lung tissue of wild-type (WT) mice, in association with increases in nuclear RelA and RelB, components of the classical and alternative NF-κB pathway, respectively, in the bronchiolar epithelium. In contrast, CC10-IκBαSR mice displayed marked decreases in nuclear RelA and RelB and mRNA expression of proinflammatory mediators compared with WT mice. After 15 challenges with HDM, WT mice exhibited increases in inflammation, AHR, mucus metaplasia, and peribronchiolar fibrosis. CC10-IκBαSR transgenic mice displayed marked decreases in neutrophilic infiltration, tissue damping, and elastance parameters, in association will less peribronchiolar fibrosis and decreases in nuclear RelB in lung tissue. However, central airway resistance and mucus metaplasia remained elevated in CC10-IκBαSR transgenic mice, in association with the continued presence of lymphocytes, and partial decreases in eosinophils and IL-13. The current study demonstrates that following airway exposure with an asthma-relevant allergen, activation of classical and alternative NF-κB pathways occurs within the airway epithelium and may coordinately contribute to allergic inflammation, AHR, and fibrotic airway remodeling.
Department of Pathology, University of Vermont College of Medicine, Burlington, VT 05405.
Jane E
JE
Tully
Sidra M
SM
Hoffman
Karolyn G
KG
Lahue
James D
JD
Nolin
Vikas
V
Anathy
Lennart K A
LK
Lundblad
Nirav
N
Daphtary
Minara
M
Aliyeva
Kendall E
KE
Black
Anne E
AE
Dixon
Matthew E
ME
Poynter
Charles G
CG
Irvin
Yvonne M W
YM
Janssen-Heininger
D000281:Administration, Intranasal; D056151:Airway Remodeling / Q000276:immunology; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage / Q000633:toxicity*; D055745:Bronchioles / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D004804:Eosinophils / Q000276:immunology; D004847:Epithelial Cells / Q000378:metabolism*; D004848:Epithelium / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology; D039981:Pyroglyphidae / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016037:Single-Blind Method; D014598:Uteroglobin / Q000235:genetics
D039741:Antigens, Dermatophagoides; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D018793:Interleukin-13; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; C556390:Scgb1a1 protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D014598:Uteroglobin