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

• Published in: Thorax Vol. 73; no. 6; pp. 519 - 529
• Main Authors: Milara, Javier, Ballester, Beatriz, Morell, Anselm, Ortiz, José L, Escrivá, Juan, Fernández, Estrella, Perez-Vizcaino, Francisco, Cogolludo, Angel, Pastor, Enrique, Artigues, Enrique, Morcillo, Esteban, Cortijo, Julio
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.06.2018
• Subjects: Animals; Blotting, Western; Cell Proliferation - drug effects; Cells, Cultured; Clinical trials; Cytokines; Endothelial Cells; Fluorescent Antibody Technique; Gene expression; Growth factors; Humans; Hypertension, Pulmonary - drug therapy; Hypoxia; Idiopathic Pulmonary Fibrosis - drug therapy; Immunohistochemistry; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; Kinases; Medical prognosis; Myocytes, Smooth Muscle; Phenotype; Phosphorylation; Pulmonary arteries; Pulmonary fibrosis; Pulmonary hypertension; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Small Interfering - pharmacology; Rodents; Signal Transduction; Smooth muscle; Transforming Growth Factor beta - pharmacology; Transplants & implants; Triterpenes - pharmacology; Vascular Remodeling - drug effects; Veins & arteries; Ventilation; Spain; BKCa; idiopathic pulmonary fibrosis; JAK2; pulmonary hypertension; Pulmonary artery smooth muscle cells, Pulmonary artery endothelial cells
• ISSN: 0040-6376; 1468-3296; 1468-3296
• DOI: 10.1136/thoraxjnl-2017-210728

BackgroundPulmonary 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.ObjectiveThe study of JAK2 as potential target to treat PH in IPF.Methods and resultsJAK2 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.ConclusionsJAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH.