title: Vascular effects of sildenafil in patients with pulmonary fibrosis and pulmonary hypertension: an ex vivo/in vitro study.
abstract: 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.
authors.affiliation: Dept of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain Clinical Research Unit (UIC), University General Hospital Consortium, Valencia, Spain Research Foundation of University General Hospital of Valencia, Valencia, Spain CIBERES, Health Institute Carlos III, Valencia, Spain Both authors contributed equally to this work xmilara@hotmail.com.
authors.forename: Javier
authors.initials: J
authors.lastname: Milara
authors.affiliation: Thoracic Surgery Unit, University and Polytechnic Hospital La Fe, Valencia, Spain Both authors contributed equally to this work.
authors.forename: Juan
authors.initials: J
authors.lastname: Escrivá
authors.affiliation: Dept of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Ortiz
authors.affiliation: CIBERES, Health Institute Carlos III, Valencia, Spain Respiratory Unit, University General Hospital Consortium, Valencia, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Juan
authors.affiliation: Surgery Unit, University General Hospital Consortium, Valencia, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Artigues
authors.affiliation: Dept of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain CIBERES, Health Institute Carlos III, Valencia, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Morcillo
authors.affiliation: Dept of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain Clinical Research Unit (UIC), University General Hospital Consortium, Valencia, Spain Research Foundation of University General Hospital of Valencia, Valencia, Spain CIBERES, Health Institute Carlos III, Valencia, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000737:chemistry; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008168:Lung / Q000473:pathology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism; D011651:Pulmonary Artery / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology; D011658:Pulmonary Fibrosis / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000737:chemistry; D015398:Signal Transduction; D000068677:Sildenafil Citrate / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014661:Vasoconstriction; D014665:Vasodilator Agents
chemical_list: D053773:Transforming Growth Factor beta1; D014665:Vasodilator Agents; D001761:Bleomycin; D012701:Serotonin; D000068677:Sildenafil Citrate