Vascular effects of sildenafil in patients with pulmonary fibrosis and pulmonary hypertension: an ex vivo/in vitro study

被引:28
|
作者
Milara, Javier [1 ,2 ,3 ,4 ]
Escriva, Juan [5 ]
Luis Ortiz, Jose [1 ]
Juan, Gustavo [4 ,6 ]
Artigues, Enrique [7 ]
Morcillo, Esteban [1 ,4 ]
Cortijo, Julio [1 ,2 ,3 ,4 ]
机构
[1] Univ Valencia, Fac Med, Dept Pharmacol, Valencia, Spain
[2] Univ Gen Hosp Consortium, Clin Res Unit UIC, Valencia, Spain
[3] Univ Gen Hosp Valencia, Res Fdn, Valencia, Spain
[4] Hlth Inst Carlos III, CIBERES, Valencia, Spain
[5] Univ & Polytech Hosp La Fe, Thorac Surg Unit, Valencia, Spain
[6] Univ Gen Hosp Consortium, Resp Unit, Valencia, Spain
[7] Univ Gen Hosp Consortium, Surg Unit, Valencia, Spain
关键词
ARTERIAL-HYPERTENSION; LUNG FIBROSIS; NITRIC-OXIDE; CONTROLLED-TRIAL; CIGARETTE-SMOKE; SMOOTH-MUSCLE; INHIBITION; EXPRESSION; EXERCISE; DISEASE;
D O I
10.1183/13993003.01259-2015
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
Sildenafil improves the 6-min walking distance in patients with idiopathic pulmonary fibrosis (IPF) and right-sided ventricular systolic dysfunction. We analysed the previously unexplored role of sildenafil on vasoconstriction and remodelling of pulmonary arteries from patients with IPF and pulmonary hypertension (PH) ex vivo. Pulmonary arteries from 18 donors without lung disease, nine IPF, eight PH+IPF and four PH patients were isolated to measure vasodilator and anti-contractile effects of sildenafil in isometric organ bath. Ventilation/perfusion was explored in an animal model of bleomycin lung fibrosis. Sildenafil relaxed serotonin (5-HT) pre-contracted pulmonary arteries in healthy donors and IPF patients and, to a lesser extent, in PH+IPF and PH. Sildenafil inhibited 5-HT dose-response contraction curve mainly in PH+IPF and PH, but not in healthy donors. Sildenafil did not impair the ventilation/perfusion mismatching induced by bleomycin. Pulmonary arteries from PH+IPF patients showed a marked expression of phosphodiesterse-5 and extracellular matrix components. Sildenafil inhibited pulmonary artery endothelial and smooth muscle cell to mesenchymal transition by inhibition of extracellular regulated kinases 1 and 2 (ERK1/2) and SMAD3 phosphorylation. These results suggest an absence of direct relaxant effect and a prominent anti-contractile and anti-remodelling role of sildenafil in PH+IPF pulmonary arteries that could explain the beneficial effects of sildenafil in IPF with PH phenotype.
引用
收藏
页码:1737 / 1749
页数:13
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