AMD3100 treatment attenuates pulmonary angiogenesis by reducing the c-kit (+) cells and its pro-angiogenic activity in CBDL rat lungs
AMD3100 treatment attenuates pulmonary angiogenesis by reducing the c-kit (+) cells and its pro-angiogenic activity in CBDL rat lungs
复制标题
AMD3100 治疗通过减少 CBDL 大鼠肺中的 c-kit ( ) 细胞及其促血管生成活性来减弱肺血管生成
DOI：
10.1016/j.bbadis.2017.12.011
复制
发表时间：
2018-03-01
影响因子：
6.2
通讯作者：
Lu, Kai-Zhi
中科院分区：
文献类型：
--
作者：
Shen, Cheng-Cheng;Chen, Bing;Lu, Kai-Zhi
近年来的研究表明，肺血管生成是肝肺综合征（HPS）发生发展的重要病理过程，越来越多的证据表明基质细胞衍生因子1/C-X-C趋化因子受体4 （SDF-1/CXCR4）轴通过介导c-kit +细胞的积累参与肺血管疾病。本研究旨在检测CXCR4拮抗剂AMD3100在HPS肺血管生成中的作用。以胆总管结扎（CBDL）大鼠为实验HPS模型，给予AMD3100 （1.25 mg/kg/d, ig）或0.9%生理盐水治疗3周。假大鼠胆总管暴露不结扎。分析各组c-kit +细胞计数及其血管生成相关功能、促生存信号、肺血管生成和动脉氧合。我们的研究结果显示，CBDL大鼠肺中SDF-1/CXCR4、Akt、Erk和VEGF/VEGFR2明显被激活，与对照大鼠相比，CBDL大鼠循环和肺中c-kit +细胞数量增加。此外，c-kit +细胞的血管生成相关功能和肺微血管计数也在CBDL大鼠中升高。CXCR4抑制降低了CBDL大鼠3周内的肺c-kit +细胞和微血管计数，并改善了动脉氧合。amd3100处理大鼠的肺促生存信号和促血管生成活性也下调。综上所述，AMD3100治疗可减弱CBDL大鼠的肺血管生成，并通过减少肺c-kit +细胞和抑制促生存信号来阻止HPS的发生。我们的研究为HPS的治疗提供了新的见解。
Recent studies have shown that pulmonary angiogenesis is an important pathological process in the development of hepatopulmonary syndrome (HPS), and growing evidence has indicated that Stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) axis is involved in pulmonary vascular disease by mediating the accumulation of c-kit + cells. This study aimed to test the effect of AMD3100, an antagonist of CXCR4, in HPS pulmonary angiogenesis. Common bile duct ligation (CBDL) rats were used as experimental HPS model and were treated with AMD3100 (1.25 mg/kg/day, i.p.) or 0.9% saline for 3 weeks. The sham rats underwent common bile duct exposure without ligation. The c-kit + cells accounts and its angiogenic-related functions, prosurvival signals, pulmonary angiogenesis and arterial oxygenation were analysed in these groups. Our results showed that pulmonary SDF-1/CXCR4, Akt, Erk and VEGF/VEGFR2 were significantly activated in CBDL rats, and the numbers of circulating and pulmonary c-kit + cells were increased in CBDL rats compared with control rats. Additionally, the angiogenic-related functions of c-kit + cells and pulmonary microvessel counts were also elevated in CBDL rats. CXCR4 inhibition reduced pulmonary c-kit + cells and microvessel counts and improved arterial oxygenation within 3 weeks in CBDL rats. The pulmonary prosurvival signals and pro-angiogenic activity of c-kit + cells were also down-regulated in AMD3100-treated rats. In conclusion, AMD3100 treatment attenuated pulmonary angiogenesis in CBDL rats and prevented the development of HPS via reductions in pulmonary c-kit + cells and inhibition of the prosurvival signals. Our study provides new insights in HPS treatment.