title: Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats.
abstract: BACKGROUND
  Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored.
  
  
  METHODS
  Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies.
  
  
  RESULTS
  There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.
  
  
  CONCLUSIONS
  The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT-rats.
authors.affiliation: University of Giessen Lung Centre, Giessen, Germany.
authors.forename: Bhola K
authors.initials: BK
authors.lastname: Dahal
authors.forename: Djuro
authors.initials: D
authors.lastname: Kosanovic
authors.forename: Christina
authors.initials: C
authors.lastname: Kaulen
authors.forename: Teodora
authors.initials: T
authors.lastname: Cornitescu
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.forename: Julia
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Irwin
authors.initials: I
authors.lastname: Reiss
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D004205:Cromolyn Sodium / Q000494:pharmacology; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000276:immunology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016686:Monocrotaline; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016278:Ventricular Function, Right; D020257:Ventricular Remodeling
chemical_list: D047428:Protein Kinase Inhibitors; D016686:Monocrotaline; D019009:Proto-Oncogene Proteins c-kit; D004205:Cromolyn Sodium