Absence of c-Jun NH<inf>2</inf>-terminal kinase 1 protects against house dust mite-induced pulmonary remodeling but not airway hyperresponsiveness and inflammation

van der Velden, JLJ; Hoffman, SM; Alcorn, JF; Tully, JE; Chapman, DG; Lahue, KG; Guala, AS; Lundblad, LKA; Aliyeva, M; Daphtary, N; Irvin, CG; Janssen-Heininger, YMW

Absence of c-Jun NH<inf>2</inf>-terminal kinase 1 protects against house dust mite-induced pulmonary remodeling but not airway hyperresponsiveness and inflammation

van der Velden, JLJ Hoffman, SM Alcorn, JF Tully, JE Chapman, DG

Lahue, KG Guala, AS Lundblad, LKA Aliyeva, M Daphtary, N Irvin, CG Janssen-Heininger, YMW

Permalink

Publication Type:: Journal Article
Citation:: American Journal of Physiology - Lung Cellular and Molecular Physiology, 2014, 306 (9)
Issue Date:: 2014-05-01

Closed Access

	Filename	Description	Size
	L866.full.pdf	Published Version	2.7 MB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	van der Velden, JLJ	en_US
dc.contributor.author	Hoffman, SM	en_US
dc.contributor.author	Alcorn, JF	en_US
dc.contributor.author	Tully, JE	en_US
dc.contributor.author	Chapman, DG https://orcid.org/0000-0002-8211-1817	en_US
dc.contributor.author	Lahue, KG	en_US
dc.contributor.author	Guala, AS	en_US
dc.contributor.author	Lundblad, LKA	en_US
dc.contributor.author	Aliyeva, M	en_US
dc.contributor.author	Daphtary, N	en_US
dc.contributor.author	Irvin, CG	en_US
dc.contributor.author	Janssen-Heininger, YMW	en_US
dc.date.issued	2014-05-01	en_US
dc.identifier.citation	American Journal of Physiology - Lung Cellular and Molecular Physiology, 2014, 306 (9)	en_US
dc.identifier.issn	1040-0605	en_US
dc.identifier.uri	http://hdl.handle.net/10453/118816
dc.description.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. © 2014 the American Physiological Society.	en_US
dc.relation.ispartof	American Journal of Physiology - Lung Cellular and Molecular Physiology	en_US
dc.relation.isbasedon	10.1152/ajplung.00153.2013	en_US
dc.subject.classification	Respiratory System	en_US
dc.subject.mesh	Respiratory System	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Dermatophagoides pteronyssinus	en_US
dc.subject.mesh	Bronchial Hyperreactivity	en_US
dc.subject.mesh	Pneumonia	en_US
dc.subject.mesh	JNK Mitogen-Activated Protein Kinases	en_US
dc.subject.mesh	RNA, Messenger	en_US
dc.subject.mesh	Cytokines	en_US
dc.subject.mesh	Blotting, Western	en_US
dc.subject.mesh	Immunoenzyme Techniques	en_US
dc.subject.mesh	Reverse Transcriptase Polymerase Chain Reaction	en_US
dc.subject.mesh	Transforming Growth Factor beta1	en_US
dc.subject.mesh	Airway Remodeling	en_US
dc.subject.mesh	Real-Time Polymerase Chain Reaction	en_US
dc.title	Absence of c-Jun NH<inf>2</inf>-terminal kinase 1 protects against house dust mite-induced pulmonary remodeling but not airway hyperresponsiveness and inflammation	en_US
dc.type	Journal Article
utslib.citation.volume	9	en_US
utslib.citation.volume	306	en_US
utslib.for	1116 Medical Physiology	en_US
utslib.for	0606 Physiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	9	en_US
pubs.publication-status	Published	en_US
pubs.volume	306	en_US

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. © 2014 the American Physiological Society.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/118816