title: Absence of c-Jun NH2-terminal kinase 1 protects against house dust mite-induced pulmonary remodeling but not airway hyperresponsiveness and inflammation.
abstract: Chronic allergic asthma leads to airway remodeling and subepithelial fibrosis via mechanisms not fully understood. Airway remodeling is amplified by profibrotic mediators, such as transforming growth factor-β1 (TGF-β1), which plays a cardinal role in various models of fibrosis. We recently have identified a critical role for c-Jun-NH2-terminal-kinase (JNK) 1 in augmenting the profibrotic effects of TGF-β1, linked to epithelial-to-mesenchymal transition of airway epithelial cells. To examine the role of JNK1 in house dust mite (HDM)-induced airway remodeling, we induced allergic airway inflammation in wild-type (WT) and JNK1-/- mice by intranasal administration of HDM extract. WT and JNK1-/- mice were sensitized with intranasal aspirations of HDM extract for 15 days over 3 wk. HDM caused similar increases in airway hyperresponsiveness, mucus metaplasia, and airway inflammation in WT and JNK1-/- mice. In addition, the profibrotic cytokine TGF-β1 and phosphorylation of Smad3 were equally increased in WT and JNK1-/- mice. In contrast, increases in collagen content in lung tissue induced by HDM were significantly attenuated in JNK1-/- mice compared with WT controls. Furthermore HDM-induced increases of α-smooth muscle actin (α-SMA) protein and mRNA expression as well as the mesenchymal markers high-mobility group AT-hook 2 and collagen1A1 in WT mice were attenuated in JNK1-/- mice. The let-7 family of microRNAs has previously been linked to fibrosis. HDM exposure in WT mice and primary lung epithelial cells resulted in striking decreases in let-7g miRNA that were not observed in mice or primary lung epithelial cells lacking JNK1-/- mice. Overexpression of let-7g in lung epithelial cells reversed the HDM-induced increases in α-SMA. Collectively, these findings demonstrate an important requirement for JNK1 in promoting HDM-induced fibrotic airway remodeling.
authors.affiliation: Dept. of Pathology, Univ. of Vermont Health Sciences Research Facility, Rm. 216A Burlington, VT 05405. Yvonne.janssen@uvm.edu).
authors.forename: Jos L J
authors.initials: JL
authors.lastname: van der Velden
authors.forename: Sidra M
authors.initials: SM
authors.lastname: Hoffman
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
authors.forename: Jane E
authors.initials: JE
authors.lastname: Tully
authors.forename: David G
authors.initials: DG
authors.lastname: Chapman
authors.forename: Karolyn G
authors.initials: KG
authors.lastname: Lahue
authors.forename: Amy S
authors.initials: AS
authors.lastname: Guala
authors.forename: Lennart K A
authors.initials: LK
authors.lastname: Lundblad
authors.forename: Minara
authors.initials: M
authors.lastname: Aliyeva
authors.forename: Nirav
authors.initials: N
authors.lastname: Daphtary
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D015153:Blotting, Western; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D040002:Dermatophagoides pteronyssinus / Q000472:pathogenicity*; D007124:Immunoenzyme Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D048031:JNK Mitogen-Activated Protein Kinases
keywords: airway; epithelial-to-mesenchymal transition; epithelium; fibrosis; lung