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


Autoři: Jos L. van der Velden aff001;  John F. Alcorn aff002;  David G. Chapman aff003;  Lennart K. A. Lundblad aff003;  Charles G. Irvin aff003;  Roger J. Davis aff004;  Kelly Butnor aff001;  Yvonne M. W. Janssen-Heininger aff001
Působiště autorů: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, United States of America aff001;  Children’s Hospital of Pittsburgh University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America aff002;  Departments of Medicine, University of Vermont, Burlington, Vermont, United States of America aff003;  Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226904

Souhrn

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.

Klíčová slova:

Basal cells – Collagens – Epithelial cells – Fibroblasts – Fibrosis – Mouse models – Pathogenesis – Pulmonary fibrosis


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