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JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study
  1. Javier Milara1,2,3,
  2. Beatriz Ballester3,4,
  3. Anselm Morell4,
  4. José L Ortiz4,
  5. Juan Escrivá5,
  6. Estrella Fernández6,
  7. Francisco Perez-Vizcaino3,7,
  8. Angel Cogolludo3,7,
  9. Enrique Pastor8,
  10. Enrique Artigues9,
  11. Esteban Morcillo3,4,10,
  12. Julio Cortijo3,11
  1. 1Department of Pharmacology, Faculty of Medicine, Jaume I University, Castellón de la Plana, Spain
  2. 2Pharmacy Unit, University General Hospital Consortium, Valencia, Spain
  3. 3CIBERES, Health Institute Carlos III, Valencia, Spain
  4. 4Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
  5. 5Thoracic Surgery Unit, University and Polytechnic Hospital La Fe, Valencia, Spain
  6. 6Respiratory Unit, University General Hospital Consortium, Valencia, Spain
  7. 7Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
  8. 8Department of Thoracic Surgery, University General Hospital Consortium, Valencia, Spain
  9. 9Surgery Unit, University General Hospital Consortium, Valencia, Spain
  10. 10Health Research Institute INCLIVA, Valencia, Spain
  11. 11Research and teaching Unit, University General Hospital Consortium, Valencia, Spain
  1. Correspondence to Dr Javier Milara, Unidad de Investigación Clínica, Consorcio Hospital General Universitario, Valencia E-46014, Spain; xmilara{at}


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.

  • JAK2
  • idiopathic pulmonary fibrosis
  • pulmonary hypertension
  • BKCa
  • Pulmonary artery smooth muscle cells, Pulmonary artery endothelial cells.
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  • JM and BB contributed equally.

  • Contributors Conception and design: JM, BB, AM, JLO, FP-V, AC and JC. Data acquisition: JM, JE, EP, EA, EF, AC, EM and JC. Analysis and interpretation: all authors.

  • Funding This work was supported by the grants SAF2014-55322-P (JC), SAF2011-28150 (FPV) and SAF2014-55399-R, FIS PI14/01733 (JM), FIS PI17/02158 (JM), SAF2015-65368-R (EM), CIBERES (CB06/06/0027), TRACE (TRA2009-0311; Spanish Government) and by research grants from the Regional Government Prometeo II/2013/014 (JC, EM and JM) and ACIF/2016/341 (BB) from ‘Generalitat Valenciana’.

  • Disclaimer Funding entities did not contribute to the study design or data collection, analysis and interpretation nor to the writing of the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval This study has been approved by the ethics committee of the University General Hospital of Valencia, Spain (CEIC22/2013).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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