期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 34, 期 7, 页码 1539-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.114.303821
关键词
cell- and tissue-based therapy; receptors, interleukin-8
资金
- University of Alabama at Birmingham Comprehensive Cardiovascular Center William W. Featheringill Innovative Award
- National Heart, Lung, and Blood Institute [RO1HL116727, RO1HL087980]
- American Heart Association [AHA SDG0930098N]
- Veterans Affairs Biomedical Laboratory Research & Development Service Merit Award [OMB 4040-0001]
Objective-Interleukin-8 (IL-8) receptors IL8RA and IL8RB (IL8RA/B) on neutrophil membranes bind to IL-8 with high affinity and play a critical role in neutrophil recruitment to sites of injury and inflammation. This study tested the hypothesis that administration of rat pulmonary arterial endothelial cells (ECs) overexpressing IL8RA/B can accelerate the adhesion of ECs to the injured lung and inhibit monocrotaline-induced pulmonary inflammation, arterial thickening and hypertension, and right ventricular hypertrophy. Approach and Results-The treatment groups included 10-week-old ovariectomized Sprague-Dawley rats that received subcutaneous injection of PBS (vehicle), a single injection of monocrotaline (monocrotaline alone, 60 mg/kg, SC), monocrotaline followed by intravenous transfusion of ECs transduced with the empty adenoviral vector (null-EC), and monocrotaline followed by intravenous transfusion of ECs overexpressing IL8RA/B (1.5x10(6) cells/rat). Two days or 4 weeks after monocrotaline treatment, endothelial nitric oxide synthase, inducible nitric oxide synthase, cytokine-induced neutrophil chemoattractant-2 beta (IL-8 equivalent in rat), and monocyte chemoattractant protein-1 expression, neutrophil and macrophage infiltration into pulmonary arterioles, and arteriolar and alveolar morphology were measured by histological and immunohistochemical techniques. Proinflammatory cytokine/chemokine protein levels were measured by Multiplex rat-specific magnetic bead-based sandwich immunoassay in total lung homogenates. Transfusion of ECs overexpressing IL8RA/B significantly reduced monocrotaline-induced neutrophil infiltration and proinflammatory mediator (IL-8, monocyte chemoattractant protein-1, inducible nitric oxide synthase, cytokine-induced neutrophil chemoattractant, and macrophage inflammatory protein-2) expression in lungs and pulmonary arterioles and alveoli, pulmonary arterial pressure, and pulmonary arterial and right ventricular hypertrophy and remodeling. Conclusions-These provocative findings suggest that targeted delivery of ECs overexpressing IL8RA/B is effective in repairing the injured pulmonary vasculature.
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