c-Jun N-terminal kinase 1 is required for the development of pulmonary fibrosis.
Collagen deposition is observed in a diverse set of pulmonary diseases, and the unraveling of the molecular signaling pathways that facilitate collagen deposition represents an ongoing area of investigation. The stress-activated protein kinase, c-Jun N-terminal kinase 1 (JNK1), is activated by a large variety of cellular stresses and environmental insults. Recent work from our laboratory demonstrated the critical role of JNK1 in epithelial to mesenchymal transition. The goal of the present study was to examine the involvement of JNK1 in subepithelial collagen deposition in mice subjected to models of allergic airways disease and interstitial pulmonary fibrosis. Activation of JNK was slightly enhanced in lungs from mice subjected to sensitization and challenge with ovalbumin (Ova), and predominant localization of phospho-JNK was observed in the bronchial epithelium. While mice lacking JNK1 (JNK1-/- mice) displayed enhanced lung inflammation and cytokine production compared with wild-type (WT) mice, JNK1-/- mice accumulated less subepithelial collagen deposition in response to antigen, and showed decreased expression of profibrotic genes compared with WT animals. Furthermore, transforming growth factor (TGF)-beta1 content in the bronchoalveolar lavage was diminished in JNK1-/- mice compared with WT animals subjected to antigen. Finally, we demonstrated that mice lacking JNK1 were protected against TGF-beta1 and bleomycin-induced pro-fibrotic gene expression and pulmonary fibrosis. Collectively, these findings demonstrate an important requirement for JNK1 in promoting collagen deposition in multiple models of fibrosis.
Alcorn
John F
JF
Department of Pathology, University of Vermont, Burlington, VT 05405, USA.
van der Velden
Jos
J
Brown
Amy L
AL
McElhinney
Brian
B
Irvin
Charles G
CG
Janssen-Heininger
Yvonne M W
YM
D000818:Animals; D000941:Antigens / Q000276:immunology; D001761:Bleomycin; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D007114:Immunization; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008679:Metaplasia / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000378:metabolism*; D009093:Mucus / Q000187:drug effects / Q000201:enzymology; D010047:Ovalbumin / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology
D000941:Antigens; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D010047:Ovalbumin; D003094:Collagen; D048055:Mitogen-Activated Protein Kinase 8