title: Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis.
abstract: Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form.
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany Division of Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Djuro
authors.initials: D
authors.lastname: Kosanovic
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany.
authors.forename: Himal
authors.initials: H
authors.lastname: Luitel
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany Risk Factor Modification Centre (RFMC), St. Michael's Hospital, Toronto, ON, Canada.
authors.forename: Bhola Kumar
authors.initials: BK
authors.lastname: Dahal
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany.
authors.forename: Teodora
authors.initials: T
authors.lastname: Cornitescu
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Janssen
authors.affiliation: Dept of Pharmacology, Erasmus University Rotterdam, Rotterdam, The Netherlands.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: Dept of Pharmacology, Erasmus University Rotterdam, Rotterdam, The Netherlands.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.affiliation: Dept of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark Dept of Pharmacology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Jo G R
authors.initials: JG
authors.lastname: De Mey
authors.affiliation: Dept of Pharmacology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Fazzi
authors.affiliation: Dept of Pharmacology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Schiffers
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwill, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Iglarz
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwill, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Fischli
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany.
authors.forename: Hossein Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany Max-Planck-Institute for Heart and Lung Research, Member of the German Center for Lung Research, Bad Nauheim, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Division of Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands Both authors contributed equally.
authors.forename: Irwin
authors.initials: I
authors.lastname: Reiss
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany Both authors contributed equally ralph.schermuly@innere.med.uni-giessen.de.
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000737:chemistry; D053818:Chymases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology; D007150:Immunohistochemistry; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D008407:Mast Cells / Q000201:enzymology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008647:Mesocricetus; D011651:Pulmonary Artery / Q000378:metabolism / Q000503:physiopathology; D011658:Pulmonary Fibrosis / Q000503:physiopathology*; D011863:Radioimmunoassay; D011897:Random Allocation; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D053818:Chymases; D020778:Matrix Metalloproteinase 2