Targeted delivery of pulmonary arterial endothelial cells overexpressing interleukin-8 receptors attenuates monocrotaline-induced pulmonary vascular remodeling.
Targeted delivery of pulmonary arterial endothelial cells overexpressing interleukin-8 receptors attenuates monocrotaline-induced pulmonary vascular remodeling.
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DOI：
10.1161/atvbaha.114.303821
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Xing DD
中科院分区：
文献类型：
--
作者：
Fu J;Chen YF;Zhao X;Creighton JR;Guo Y;Hage FG;Oparil S;Xing DD
中性粒细胞膜上的白细胞介素-8（IL 8）受体IL 8 RA和IL 8 RB（ILRA/B）以高亲和力结合IL 8，并在中性粒细胞募集至损伤和/或炎症部位中起关键作用。本研究验证了以下假设：给予过表达IL 8 RA/B的大鼠肺动脉内皮细胞（EC）可加速EC与损伤肺的粘附，并抑制野百合碱（MCT）诱导的肺部炎症、动脉增厚和高血压以及右心室（RV）肥大。治疗组包括10周龄卵巢切除的Sprague-Dawley大鼠，其接受s.c.注射磷酸盐缓冲盐水（溶剂）;单次注射MCT（单独MCT，60 mg/kg，s.c.）; MCT后静脉输注空腺病毒载体转导的EC（Null-EC）; MCT后静脉输注过表达IL 8 RA/B的EC（IL 8 RA/B-EC，1.5×106个细胞/大鼠）。MCT处理后2天或4周，通过组织学和免疫组织化学技术测量eNOS、iNOS、CINC-2β（大鼠中的IL 8当量）和MCP-1表达;中性粒细胞和巨噬细胞浸润到肺小动脉中，以及小动脉和肺泡形态。通过基于多重大鼠特异性磁珠的夹心免疫测定法测量总肺匀浆中的促炎细胞因子/趋化因子蛋白水平。输注IL 8 RA/B-EC显著降低MCT诱导的中性粒细胞浸润和肺和肺小动脉及肺泡中促炎介质（IL-8、MCP-1、iNOS、CINC和MIP-2）的表达、肺动脉压以及肺小动脉和RV肥大和重塑。这些激动人心的发现表明，靶向递送过表达IL 8 RA/B的EC在修复受损的肺血管系统中是有效的。
Interleukin-8 (IL8) receptors IL8RA and IL8RB (ILRA/B) on neutrophil membranes bind to IL8 with high affinity and play a critical role in neutrophil recruitment to sites of injury and/or 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 (MCT)-induced pulmonary inflammation, arterial thickening and hypertension, and right ventricular (RV) hypertrophy. The treatment groups included 10-wk-old ovariectomized Sprague-Dawley rats that received s.c. injection of phosphate-buffered-saline (Vehicle); a single injection of MCT (MCT alone, 60 mg/kg, s.c.); MCT followed by i.v. transfusion of ECs transduced with the empty adenoviral vector (Null-EC); and MCT followed by i.v. transfusion of ECs overexpressing IL8RA/B (IL8RA/B-EC, 1.5×106 cells/rat). Two days or 4 wks after MCT treatment, eNOS, iNOS, CINC-2β (IL8 equivalent in rat) and MCP-1 expression; neutrophil and macrophage infiltration into pulmonary arterioles, and arteriolar and alveolar morphology were measured by histological and immunohistochemical techniques. Pro-inflammatory cytokine/chemokine protein levels were measured by Multiplexed rat specific magnetic beads based sandwich immunoassay in total lung homogenates. Transfusion of IL8RA/B-ECs significantly reduced MCT-induced neutrophil infiltration and pro-inflammatory mediator (IL-8, MCP-1, iNOS, CINC and MIP-2) expression in lungs and pulmonary arterioles and alveoli, pulmonary artery pressure, and pulmonary arteriole and RV hypertrophy and remodeling. These provocative findings suggest that targeted delivery of ECs overexpressing IL8RA/B is effective in repairing the injured pulmonary vasculature.