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Thorax. 2018 Jun;73(6):519-529. doi: 10.1136/thoraxjnl-2017-210728. Epub 2018 Feb 10.

JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study.

Author information

1
Department of Pharmacology, Faculty of Medicine, Jaume I University, Castellón de la Plana, Spain.
2
Pharmacy Unit, University General Hospital Consortium, Valencia, Spain.
3
CIBERES, Health Institute Carlos III, Valencia, Spain.
4
Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
5
Thoracic Surgery Unit, University and Polytechnic Hospital La Fe, Valencia, Spain.
6
Respiratory Unit, University General Hospital Consortium, Valencia, Spain.
7
Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
8
Department of Thoracic Surgery, University General Hospital Consortium, Valencia, Spain.
9
Surgery Unit, University General Hospital Consortium, Valencia, Spain.
10
Health Research Institute INCLIVA, Valencia, Spain.
11
Research and teaching Unit, University General Hospital Consortium, Valencia, Spain.
#
Contributed equally

Abstract

BACKGROUND:

Pulmonary hypertension (PH) is a common disorder in patients with idiopathic pulmonary fibrosis (IPF) and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation (V)/perfusion (Q) mismatching and oxygen desaturation. Janus kinase type 2 (JAK2) is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown.

OBJECTIVE:

The study of JAK2 as potential target to treat PH in IPF.

METHODS AND RESULTS:

JAK2 expression was increased in pulmonary arteries (PAs) from IPF (n=10; 1.93-fold; P=0.0011) and IPF+PH (n=9; 2.65-fold; P<0.0001) compared with PA from control subjects (n=10). PA remodelling was evaluated in human pulmonary artery endothelial cells (HPAECs) and human pulmonary artery smooth muscle cells (HPASMCs) from patients with IPF in vitro treated with the JAK2 inhibitor JSI-124 or siRNA-JAK2 and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-JAK2 inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. JAK2 inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel (BKCa). JAK2 inhibition activated BKCa channels and reduced intracellular Ca2+. JSI-124 1 mg/kg/day, reduced bleomycin-induced lung fibrosis, PA remodelling, right ventricular hypertrophy, PA hypertension and V/Q mismatching in rats. The animal studies followed the ARRIVE guidelines.

CONCLUSIONS:

JAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH.

KEYWORDS:

BKCa; JAK2; Pulmonary artery smooth muscle cells, Pulmonary artery endothelial cells.; idiopathic pulmonary fibrosis; pulmonary hypertension

PMID:
29440315
DOI:
10.1136/thoraxjnl-2017-210728
[Indexed for MEDLINE]

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