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 ß1 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.
Subject(s)
Chymases/metabolism , Chymases/physiology , Hypertension, Pulmonary/physiopathology , Lung/physiopathology , Pulmonary Fibrosis/physiopathology , Animals , Bleomycin/chemistry , Chymases/antagonists & inhibitors , Disease Models, Animal , Endothelin-1/metabolism , Enzyme-Linked Immunosorbent Assay , Hemodynamics , Humans , Hypertrophy, Right Ventricular/enzymology , Immunohistochemistry , Lung/enzymology , Lung/metabolism , Mast Cells/enzymology , Matrix Metalloproteinase 2/metabolism , Mesocricetus , Pulmonary Artery/metabolism , Pulmonary Artery/physiopathology , Radioimmunoassay , Random Allocation , Transforming Growth Factor beta1/metabolismABSTRACT
BACKGROUND: Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats. METHODS: Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed. RESULTS: The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling. CONCLUSION: The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.
Subject(s)
Antihypertensive Agents/pharmacology , Hypertension, Pulmonary/drug therapy , Hypertrophy, Right Ventricular/drug therapy , Isoxazoles/pharmacology , Monocrotaline , Sulfones/pharmacology , Administration, Oral , Animals , Antihypertensive Agents/administration & dosage , Disease Models, Animal , Echocardiography, Doppler , Endothelin A Receptor Antagonists , Fibrosis , Hemodynamics/drug effects , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/diagnostic imaging , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/physiopathology , Hypertrophy, Right Ventricular/diagnostic imaging , Hypertrophy, Right Ventricular/metabolism , Hypertrophy, Right Ventricular/physiopathology , Isoxazoles/administration & dosage , Male , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , Rats , Rats, Sprague-Dawley , Receptor, Endothelin A/metabolism , Sulfones/administration & dosage , Time Factors , Ventricular Function, Right/drug effects , Ventricular Remodeling/drug effectsABSTRACT
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.
Subject(s)
Cell Degranulation , Hypertension, Pulmonary/immunology , Lung/immunology , Mast Cells/immunology , Animals , Cell Degranulation/drug effects , Cromolyn Sodium/pharmacology , Disease Models, Animal , Familial Primary Pulmonary Hypertension , Female , Hemodynamics , Humans , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/physiopathology , Hypertrophy, Right Ventricular/immunology , Hypertrophy, Right Ventricular/physiopathology , Lung/blood supply , Lung/drug effects , Lung/metabolism , Male , Mast Cells/drug effects , Mast Cells/metabolism , Monocrotaline , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Proto-Oncogene Proteins c-kit/metabolism , Rats , Rats, Sprague-Dawley , Ventricular Function, Right , Ventricular RemodelingABSTRACT
RATIONALE: Epidermal growth factor (EGF) and its receptors play a role in cell proliferation and survival and are implicated in the pathobiology of pulmonary arterial hypertension (PAH). OBJECTIVES: To study the role of EGF inhibition on experimental pulmonary hypertension. METHODS: We investigated (1) the effects of three clinically approved EGF receptor (EGFR) antagonists in vitro on rat pulmonary arterial smooth muscle cell proliferation and in vivo on experimental pulmonary hypertension (PH) induced by monocrotaline injection in rats and by chronic hypoxia in mice, and (2) the expression of EGFR in the lung tissues from experimental and clinical PH. MEASUREMENTS AND MAIN RESULTS: The EGFR inhibitors gefitinib, erlotinib, and lapatinib inhibited the EGF-induced proliferation of pulmonary arterial smooth muscle cells. In rats with established PH, gefitinib and erlotinib significantly reduced right ventricular systolic pressure and right ventricular hypertrophy. In addition, the medial wall thickness and muscularization of pulmonary arteries were improved. In contrast, lapatinib did not provide therapeutic benefit. These EGFR antagonists at their highest tolerable dose did not yield significant improvement in right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in mice with chronic hypoxic PH. Moreover, no significant alteration in the EGFR expression was detected in the lung tissues from patients with idiopathic PAH. CONCLUSIONS: The partial therapeutic efficacy of the EGFR antagonists in animal models of pulmonary hypertension and the absence of significant alteration in EGFR expression in the lungs from patients with idiopathic PAH suggest that EGFRs do not represent a promising target for the treatment of pulmonary hypertension.
