The JAK2 pathway is activated in idiopathic pulmonary fibrosis

Javier Milara,Juan Escrivá,P Montero,Gracia Hernandez,Beatriz Ballester,Julio Cortijo,Maria Molina-Molina,José M Lloris,Esteban Morcillo,Inés Roger,Anselm Morell

doi:10.1186/s12931-018-0728-9

Abstract

BackgroundIdiopathic 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 resultsJAK2/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.ConclusionsJAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease.

Highlights

Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies
Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) are activated in IPF, and their dual inhibition may be an attractive strategy for treating this disease
Whereas the active phosphorylated forms of JAK2 and STAT3 were upregulated in IPF lung tissue, the levels

Summary

Introduction

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. IPF is characterized by heterogeneous pulmonary lesions at different stages of evolution, with foci of proliferative fibroblasts and myofibroblasts, abnormal lung epithelial cells, and an overwhelming matrix accumulation in the lung interstitium [2]. The origins of the invasive lung myofibroblasts and their activation are unknown but are probably multiple, including activation of lung resident fibroblasts, recruitment of circulating fibrocyte blood mesenchymal precursors, and mesenchymal transformations of alveolar type II epithelial cells (ATII), endothelial cells, pericytes, and mesothelial cells [3]

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