Abstract
The combination of chronic hypoxia and treatment of rats with the vascular endothelial growth factor (VEGF) receptor blocker, SU5416, induces pulmonary angio-obliteration, resulting in severe pulmonary arterial hypertension (PAH). Inflammation is thought to contribute to the pathology of PAH. Allergic inflammation caused by ovalbumin (OVA) immunization causes muscularization of pulmonary arteries, but not severe PAH. Whether disturbance of the immune system and allergic inflammation in the setting of lung endothelial cell apoptosis causes PAH is unknown. We investigated the effects of OVA-allergic inflammation on the development of PAH initiated by VEGF blockade-induced lung endothelial cell apoptosis. OVA-immunized rats were treated with SU5416 to induce pulmonary vascular endothelial cell apoptosis. The combination of OVA and SU5416 treatment resulted in severe angio-obilterative PAH, accompanied by increased IL-6 expression in the lungs. c-Kit(+) and Sca-1(+) cells were found in and around the lung vascular lesions. Pan-caspase inhibiton, dexamethasone treatment, and depletion of B-lymphocytes using an anti-CD20 antibody suppressed this remodeling. OVA immunization also increased lung tissue hypoxia-induced factor-1α and VEGF expression. Our results also suggest that the increased expression of hypoxia-induced factor-1α and IL-6 induced by the allergic lung inflammation may be a component of the pathogenesis of PAH.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antilymphocyte Serum / pharmacology
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Apoptosis / drug effects
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Asparagine / analogs & derivatives
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Asparagine / pharmacology
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Asparagine / therapeutic use
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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Caspase Inhibitors / pharmacology
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Caspase Inhibitors / therapeutic use
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Cell Proliferation
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Dexamethasone / pharmacology
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Dexamethasone / therapeutic use
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Disease Models, Animal*
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Hemodynamics
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Hypertension, Pulmonary / chemically induced*
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Hypertension, Pulmonary / immunology
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Hypertension, Pulmonary / prevention & control
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Immunization*
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Indoles / adverse effects*
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Indoles / pharmacology
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Interleukin-6 / metabolism
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Lung / blood supply
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Lung / drug effects
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Lung / immunology
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Lung / pathology
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Male
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Ovalbumin / immunology*
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Proliferating Cell Nuclear Antigen / metabolism
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Pulmonary Artery / drug effects
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Pulmonary Artery / pathology
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Pulmonary Artery / physiopathology
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Pyrroles / adverse effects*
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Pyrroles / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Antilymphocyte Serum
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Caspase Inhibitors
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1, alpha Subunit
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Indoles
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Interleukin-6
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Proliferating Cell Nuclear Antigen
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Pyrroles
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Vascular Endothelial Growth Factor A
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benzyloxycarbonyl-asparagine
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vascular endothelial growth factor A, rat
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Asparagine
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Semaxinib
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Dexamethasone
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Ovalbumin
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Receptors, Vascular Endothelial Growth Factor