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JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study
Data de publicació:
Autors de IIS La Fe
Autors aliens a IIS La Fe
- Milara, J
- Ballester, B
- Morell, A
- Ortiz, JL
- Fernandez, E
- Perez-Vizcaino, F
- Cogolludo, A
- Pastor, E
- Artigues, E
- Morcillo, E
- Cortijo, J
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 T he 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 (BK Ca). JAK2 inhibition activated BK Ca 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 ARIVE guidelines. Conclusions JAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH.
Dades de la publicació
- ISSN/ISSNe:
- 0040-6376, 1468-3296
- Tipus:
- Article
- Pàgines:
- 519-529
- PubMed:
- 29440315
- Factor d'Impacte:
- 3,697 SCImago ℠
- Quartil:
- Q1 SCImago ℠
Thorax BMJ PUBLISHING GROUP
Cites Rebudes en Web of Science: 48
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- No hi ha documents
Filiacions
Keywords
- BKCa; JAK2; Pulmonary artery smooth muscle cells, Pulmonary artery endothelial cells.; idiopathic pulmonary fibrosis; pulmonary hypertension
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