Nabah Yafa Naim Abu, Mateo Teresa, Estellés Rossana, Mata Manuel, Zagorski John, Sarau Henry, Cortijo Julio, Morcillo Esteban J, Jose Peter J, Sanz Maria-Jesus
Department of Pharmacology,Faculty of Medicine, University of Valencia, Valencia, Spain.
Circulation. 2004 Dec 7;110(23):3581-6. doi: 10.1161/01.CIR.0000148824.93600.F3. Epub 2004 Nov 29.
Angiotensin II (Ang II) is implicated in the development of cardiac ischemic disorders in which prominent neutrophil accumulation occurs. Ang II can be generated intravascularly by the renin-angiotensin system or extravascularly by mast cell chymase. In this study, we characterized the ability of Ang II to induce neutrophil accumulation.
Intraperitoneal administration of Ang II (1 nmol/L) induced significant neutrophil recruitment within 4 hours (13.3+/-2.3x10(6) neutrophils per rat versus 0.7+/-0.5x10(6) in control animals), which disappeared by 24 hours. Maximal levels of CXC chemokines were detected 1 hour after Ang II injection (577+/-224 pmol/L cytokine-inducible neutrophil chemoattractant [CINC]/keratinocyte-derived chemokine [KC] versus 5+/-3, and 281+/-120 pmol/L macrophage inflammatory protein [MIP-2] versus 14+/-6). Intravital microscopy within the rat mesenteric microcirculation showed that the short-term (30 to 60 minutes) leukocyte-endothelial cell interactions induced by Ang II were attenuated by an anti-rat CINC/KC antibody and nearly abolished by the CXCR2 antagonist SB-517785-M. In human umbilical vein endothelial cells (HUVECs) or human pulmonary artery media in culture, Ang II induced interleukin (IL)-8 mRNA expression at 1, 4, and 24 hours and the release of IL-8 at 4 hours through interaction with Ang II type 1 receptors. When HUVECs were pretreated with IL-1 for 24 hours to promote IL-8 storage in Weibel-Palade bodies, the Ang II-induced IL-8 release was more rapid and of greater magnitude.
Ang II provokes rapid neutrophil recruitment, mediated through the release of CXC chemokines such as CINC/KC and MIP-2 in rats and IL-8 in humans, and may contribute to the infiltration of neutrophils observed in acute myocardial infarction.
血管紧张素II（Ang II）与心肌缺血性疾病的发生有关，此类疾病中会出现显著的中性粒细胞积聚。Ang II可由肾素-血管紧张素系统在血管内生成，也可由肥大细胞糜蛋白酶在血管外生成。在本研究中，我们对Ang II诱导中性粒细胞积聚的能力进行了特性描述。
腹腔注射Ang II（1 nmol/L）在4小时内诱导了显著的中性粒细胞募集（每只大鼠13.3±2.3×10⁶个中性粒细胞，而对照动物为0.7±0.5×10⁶个），24小时后这种现象消失。Ang II注射1小时后检测到CXC趋化因子的最高水平（细胞因子诱导的中性粒细胞趋化因子[CINC]/角质形成细胞衍生趋化因子[KC]为577±224 pmol/L，而对照为5±3；巨噬细胞炎性蛋白[MIP-2]为281±120 pmol/L，而对照为14±6）。大鼠肠系膜微循环的活体显微镜检查显示，Ang II诱导的短期（30至60分钟）白细胞-内皮细胞相互作用被抗大鼠CINC/KC抗体减弱，而被CXCR2拮抗剂SB-517785-M几乎完全消除。在培养的人脐静脉内皮细胞（HUVECs）或人肺动脉中膜中，Ang II通过与1型血管紧张素II受体相互作用，在1、4和24小时诱导白细胞介素（IL）-8 mRNA表达，并在4小时诱导IL-8释放。当用IL-1预处理HUVECs 24小时以促进IL-8储存在魏尔-帕拉德小体中时，Ang II诱导的IL-8释放更快且幅度更大。
Ang II通过释放大鼠体内的CXC趋化因子如CINC/KC和MIP-2以及人类体内的IL-8，引发快速的中性粒细胞募集，这可能促成了急性心肌梗死中观察到的中性粒细胞浸润。
