Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats |
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| Authors: | Bhola K Dahal Djuro Kosanovic Christina Kaulen Teodora Cornitescu Rajkumar Savai Julia Hoffmann Irwin Reiss Hossein A Ghofrani Norbert Weissmann Wolfgang M Kuebler Werner Seeger Friedrich Grimminger Ralph T Schermuly |
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| Institution: | 1.University of Giessen Lung Centre (UGLC), Giessen, Germany;2.Institute of Physiology, Charité-Universitaetsmedizin Berlin, Germany;3.Department of Pediatric Surgical Intensive Care, Erasmus MC-Sophia Children''s Hospital, Rotterdam, Netherlands;4.The Keenan Research Centre at the Li Ka Shing Knowledge Institute of St. Michael''s Hospital, Toronto, Canada;5.Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany |
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| Abstract: | BackgroundMast 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.MethodsPulmonary 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.ResultsThere 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.ConclusionsThe 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. |
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