The JAK2 pathway is activated in idiopathic pulmonary fibrosis
Authors: Julio Cortijo
P Montero
Juan Escrivá
Javier Milara
Inés Roger
Esteban Morcillo
José M Lloris
Maria Molina-Molina
Gracia Hernandez
Anselm Morell
Beatriz Ballester
Journal: Respiratory Research (2018)
Discipline: CLINICAL MEDICINE
Keywords: Alveolar type II epithelial cells; Idiopathic pulmonary fibrosis; JAK2; Lung fibroblasts; STAT3.
Affiliations: Department of Pharmacology, Faculty of Medicine, Jaume I University, Castellon de la Plana, Spain. ., Pharmacy Unit, University General Hospital Consortium, Valencia, Spain. ., CIBERES, Health Institute Carlos III, Valencia, Spain. ., Unidad de Investigación Clínica, Consorcio Hospital General Universitario, Avenida Tres Cruces s/n, E-46014, Valencia, Spain. ., Departmnt of Biotechnology, Valencia Polytechnic University of Valencia, Valencia, Spain., Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain., CIBERES, Health Institute Carlos III, Valencia, Spain., Thoracic Surgery Unit, University and Polytechnic Hospital La Fe, Valencia, Spain., Department of Medicine, Faculty of Medicine, University of Valencia, Valencia, Spain., Unidad Funcional de Intersticio Pulmonar (UFIP), Servicio de Neumología, Hospital Universitario de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Health Research Institute INCLIVA, Valencia, Spain., Research and Teaching Unit, University General Hospital Consortium, Valencia, Spain.

Abstract:  Background: Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease. Methods and results: JAK2/p-JAK2 and STAT3/pSTAT3 expression was evaluated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue (n = 10) both proteins were upregulated in the lung tissue of IPF patients (n = 12). Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-JAK2/p-STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were JAK2 and STAT3 activation and several markers of fibrosis, autophagy, senescence, and anti-apoptosis. Conclusions: JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease. 

Retracted: No

PubPeer comments:
 Fig 1 C. A legend would be helpful why this duplication is being necessary. Scale bar unlikely to be correct. ![file] ,