Airway epithelial specific deletion of Jun-N-terminal kinase 1 attenuates pulmonary fibrosis in two independent mouse models

van der Velden, JL; Alcorn, JF; Chapman, DG; Lundblad, LKA; Irvin, CG; Davis, RJ; Butnor, K; Janssen-Heininger, YMW

Airway epithelial specific deletion of Jun-N-terminal kinase 1 attenuates pulmonary fibrosis in two independent mouse models

van der Velden, JL

Alcorn, JF Chapman, DG

Lundblad, LKA Irvin, CG Davis, RJ Butnor, K Janssen-Heininger, YMW

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Publication Type:: Journal Article
Citation:: PLoS ONE, 2020, 15 (1)
Issue Date:: 2020-01-01

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Field	Value	Language
dc.contributor.author	van der Velden, JL https://orcid.org/0000-0002-2451-3180	en_US
dc.contributor.author	Alcorn, JF	en_US
dc.contributor.author	Chapman, DG https://orcid.org/0000-0002-8211-1817	en_US
dc.contributor.author	Lundblad, LKA	en_US
dc.contributor.author	Irvin, CG	en_US
dc.contributor.author	Davis, RJ	en_US
dc.contributor.author	Butnor, K	en_US
dc.contributor.author	Janssen-Heininger, YMW	en_US
dc.date.available	2019-12-07	en_US
dc.date.issued	2020-01-01	en_US
dc.identifier.citation	PLoS ONE, 2020, 15 (1)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/138426
dc.description.abstract	© 2020 van der Velden et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The stress-induced kinase, c-Jun-N-terminal kinase 1 (JNK1) has previously been implicated in the pathogenesis of lung fibrosis. However, the exact cell type(s) wherein JNK1 exerts its pro-fibrotic role(s) remained enigmatic. Herein we demonstrate prominent activation of JNK in bronchial epithelia using the mouse models of bleomycin- or AdTGFβ1-induced fibrosis. Furthermore, in lung tissues of patients with idiopathic pulmonary fibrosis (IPF), active JNK was observed in various regions including type I and type II pneumocytes and fibroblasts. No JNK activity was observed in adjacent normal tissue or in normal control tissue. To address the role of epithelial JNK1, we ablated Jnk1 form bronchiolar and alveolar type II epithelial cells using CCSP-directed Cre recombinase-mediated ablation of LoxP-flanked Jnk1 alleles. Our results demonstrate that ablation of Jnk1 from airway epithelia resulted in a strong protection from bleomycin- or adenovirus expressing active transforming growth factor beta-1 (AdTGFβ1)-induced fibrosis. Ablation of the Jnk1 allele at a time when collagen increases were already present showed a reversal of existing increases in collagen content. Epithelial Jnk1 ablation resulted in attenuation of mesenchymal genes and proteins in lung tissue and preserved expression of epithelial genes. Collectively, these data suggest that epithelial JNK1 contributes to the pathogenesis of pulmonary fibrosis. Given the presence of active JNK in lungs from patients with IPF, targeting JNK1 in airway epithelia may represent a potential treatment strategy to combat this devastating disease.	en_US
dc.relation.ispartof	PLoS ONE	en_US
dc.relation.isbasedon	10.1371/journal.pone.0226904	en_US
dc.subject.classification	General Science & Technology	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Bleomycin	en_US
dc.subject.mesh	Dependovirus	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Epithelial Cells	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Gene Deletion	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Idiopathic Pulmonary Fibrosis	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Mitogen-Activated Protein Kinase 8	en_US
dc.subject.mesh	Phosphorylation	en_US
dc.subject.mesh	Transforming Growth Factor beta1	en_US
dc.title	Airway epithelial specific deletion of Jun-N-terminal kinase 1 attenuates pulmonary fibrosis in two independent mouse models	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	15	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	open_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	15	en_US

Abstract:

© 2020 van der Velden et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The stress-induced kinase, c-Jun-N-terminal kinase 1 (JNK1) has previously been implicated in the pathogenesis of lung fibrosis. However, the exact cell type(s) wherein JNK1 exerts its pro-fibrotic role(s) remained enigmatic. Herein we demonstrate prominent activation of JNK in bronchial epithelia using the mouse models of bleomycin- or AdTGFβ1-induced fibrosis. Furthermore, in lung tissues of patients with idiopathic pulmonary fibrosis (IPF), active JNK was observed in various regions including type I and type II pneumocytes and fibroblasts. No JNK activity was observed in adjacent normal tissue or in normal control tissue. To address the role of epithelial JNK1, we ablated Jnk1 form bronchiolar and alveolar type II epithelial cells using CCSP-directed Cre recombinase-mediated ablation of LoxP-flanked Jnk1 alleles. Our results demonstrate that ablation of Jnk1 from airway epithelia resulted in a strong protection from bleomycin- or adenovirus expressing active transforming growth factor beta-1 (AdTGFβ1)-induced fibrosis. Ablation of the Jnk1 allele at a time when collagen increases were already present showed a reversal of existing increases in collagen content. Epithelial Jnk1 ablation resulted in attenuation of mesenchymal genes and proteins in lung tissue and preserved expression of epithelial genes. Collectively, these data suggest that epithelial JNK1 contributes to the pathogenesis of pulmonary fibrosis. Given the presence of active JNK in lungs from patients with IPF, targeting JNK1 in airway epithelia may represent a potential treatment strategy to combat this devastating disease.

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http://hdl.handle.net/10453/138426