Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
J Mol Cell Cardiol. 2010 Sep;49(3):469-81. doi: 10.1016/j.yjmcc.2010.02.003. Epub 2010 Feb 17.
We systematically investigated serial efficacy of granulocyte colony-stimulating factor (G-CSF) therapy upon experimental autoimmune myocarditis (EAM) in rats treated with and without the inhibition of nitric oxide (NO) with the analyses of tissue regeneration. G-CSF could mobilize multipotent progenitor cells of bone marrow into the peripheral blood and may improve ventricular function. A rat model of porcine myosin-induced EAM was used. After the immunization of myosin, G-CSF (10 microg/kg/day) or saline was injected intraperitoneally on days 0-21 in experiment 1 and on days 21-42 in experiment 2. Additional myosin-immunized rats were orally given 25 mg/kg/day of N(G)-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide synthase (NOS), in each experiment (each group; n=8-21). Serum cytokines and peripheral blood cell counts were measured in each group. In experiment 1, G-CSF treatment aggravated cardiac pathology associated with increased macrophage inflammatory protein-2 (MIP-2) and interleukin-6 (IL-6) levels and enhanced superoxide production. In experiment 2, G-CSF treatment reduced the severity of myocarditis with increased capillary density and improved left ventricular ejection fraction. In the rats with EAM treated with G-CSF associated with oral L-NAME treatment in experiment 2, the severity of myocarditis was not reduced. Myocardial c-kit(+) cells were demonstrated only in G-CSF-treated group in experiment 2 but not in other groups. G-CSF has differential effects on EAM in rats associated with the modulation of cytokine network. The overwhelming superoxide production by G-CSF administration in the acute stage may worsen the disease. G-CSF therapy improved cardiac function via NO system in a rat model of myocarditis in the chronic stage, but not in the acute stage, possibly through the myocardial regeneration and acceleration of healing process.
我们系统地研究了粒细胞集落刺激因子（G-CSF）治疗在实验性自身免疫性心肌炎（EAM）中的连续疗效，同时分析了组织再生情况。G-CSF 可以动员骨髓中的多能祖细胞进入外周血，并可能改善心室功能。使用猪肌球蛋白诱导的大鼠 EAM 模型。在肌球蛋白免疫后，在实验 1 中于第 0-21 天和实验 2 中于第 21-42 天每天腹腔内注射 10 μg/kg 的 G-CSF 或生理盐水。在每个实验中（每组 n=8-21），给另外的肌球蛋白免疫大鼠口服 25 mg/kg/天的 N(G)-硝基-L-精氨酸甲酯（L-NAME），一种一氧化氮合酶（NOS）抑制剂。测量每组的血清细胞因子和外周血细胞计数。在实验 1 中，G-CSF 治疗加重了与巨噬细胞炎症蛋白-2（MIP-2）和白细胞介素-6（IL-6）水平升高相关的心脏病理学，并增强了超氧化物的产生。在实验 2 中，G-CSF 治疗减轻了心肌炎的严重程度，增加了毛细血管密度并改善了左心室射血分数。在实验 2 中，与口服 L-NAME 治疗相关的 EAM 大鼠中，G-CSF 治疗并未减轻心肌炎的严重程度。在实验 2 中，只有 G-CSF 治疗组显示心肌 c-kit(+)细胞，但在其他组中则没有。G-CSF 对大鼠 EAM 具有不同的影响，与细胞因子网络的调节有关。在急性期给予 G-CSF 会产生大量超氧化物，可能会使病情恶化。在慢性阶段，G-CSF 治疗通过 NO 系统改善了心肌炎大鼠的心脏功能，但在急性期则没有，可能是通过心肌再生和加速愈合过程。
