title: Mast cell inhibition improves pulmonary vascular remodeling in pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a progressive angioproliferative disease with high morbidity and mortality. Although the histopathology is well described, its pathogenesis is largely unknown. We previously identified the increased presence of mast cells and their markers in a rat model of flow-associated PAH. The aim of this study was to test the effect of mast cell stabilization on pulmonary vascular remodeling in experimental PAH.
  
  
  METHODS
  Rats with flow-associated PAH created by monocrotaline and an aorto-caval shunt were treated with the mast cell stabilizer cromolyn and compared with untreated rats and control rats. Further, we treated a group of rats with PAH with an inhibitor (TY-51469) of chymase, one of the mast cell proteases. The effects on pulmonary vascular remodeling and hemodynamics were assessed.
  
  
  RESULTS
  Rats with PAH had increased mast cells, chymase activity, and inflammatory markers. Treatment with mast cell stabilizer attenuated pulmonary vascular remodeling but not hemodynamics. A lower pulmonary chymase activity correlated with more favorable pulmonary vascular remodeling as well as hemodynamics and inflammatory markers.
  
  
  CONCLUSIONS
  We showed in rats with PAH that mast cell stabilization attenuated pulmonary vascular remodeling and that a lower chymase activity correlated with more favorable hemodynamics and pulmonary vascular remodeling. The results of this experimental study support the concept of the use of antiinflammatory therapy by mast cell stabilizers, a group of drugs already licensed for clinical use, to attenuate disease progression in PAH.
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: b.bartelds@umcg.nl.
authors.forename: Beatrijs
authors.initials: B
authors.lastname: Bartelds
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rosa Laura E
authors.initials: RLE
authors.lastname: van Loon
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Saffloer
authors.initials: S
authors.lastname: Mohaupt
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Wijnberg
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Dickinson
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bibiche
authors.initials: B
authors.lastname: Boersma
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Janny
authors.initials: J
authors.lastname: Takens
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van Albada
authors.affiliation: Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Rolf M F
authors.initials: RMF
authors.lastname: Berger
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D053818:Chymases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004205:Cromolyn Sodium / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016686:Monocrotaline / Q000009:adverse effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D013449:Sulfonamides; C524344:TY 51469; D013876:Thiophenes; D016686:Monocrotaline; D053818:Chymases; D004205:Cromolyn Sodium