From the Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, Department of Medicine (J.F., Y.-F.C., X.Z., Y.G., F.G.H., S.O., D.D.X.) and Department of Anesthesiology, University of Alabama at Birmingham (J.R.C.); Department of Biochemistry and the Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Xinjiang, China (J.F.); and Section of Cardiology, Birmingham Veteran's Administration Medical Center, AL (F.G.H.).
Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1539-47. doi: 10.1161/ATVBAHA.114.303821. Epub 2014 May 1.
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.
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 (1.5 × 10(6) cells/rat). Two days or 4 weeks after monocrotaline treatment, endothelial nitric oxide synthase, inducible nitric oxide synthase, cytokine-induced neutrophil chemoattractant-2β (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.
These provocative findings suggest that targeted delivery of ECs overexpressing IL8RA/B is effective in repairing the injured pulmonary vasculature.
白细胞介素-8（IL-8）受体 IL8RA 和 IL8RB（IL8RA/B）在中性粒细胞膜上与 IL-8 具有高亲和力结合，并在中性粒细胞募集到损伤和炎症部位中发挥关键作用。本研究检验了这样一个假设，即给予过表达 IL8RA/B 的大鼠肺动脉内皮细胞（ECs）可加速 ECs 与受损肺的黏附，并抑制野百合碱诱导的肺炎症、动脉增厚和高血压以及右心室肥厚。
实验组包括接受皮下注射 PBS（载体）、单次注射野百合碱（野百合碱单独，60mg/kg，SC）、野百合碱后静脉输注转导空腺病毒载体的 EC（空-EC）和野百合碱后静脉输注过表达 IL8RA/B 的 EC（1.5×10（6）细胞/只）的 10 周龄去卵巢 Sprague-Dawley 大鼠。野百合碱处理后 2 天或 4 周，通过组织学和免疫组织化学技术测量内皮型一氧化氮合酶、诱导型一氧化氮合酶、细胞因子诱导的中性粒细胞趋化因子-2β（大鼠中 IL-8 的等效物）和单核细胞趋化蛋白-1 的表达、中性粒细胞和巨噬细胞浸润肺小动脉以及小动脉和肺泡形态。通过总肺匀浆中的多重大鼠特异性磁珠夹心免疫测定法测量促炎细胞因子/趋化因子蛋白水平。
这些激动人心的发现表明，过表达 IL8RA/B 的 EC 的靶向输送可有效修复受损的肺血管。
