Bone marrow-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension
Bone marrow-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension
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DOI：
10.1378/chest.127.5.1793
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发表时间：
2005-05-01
期刊：
影响因子：
9.6
通讯作者：
Fukuda, K
中科院分区：
文献类型：
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作者：
Hayashida, K;Fujita, J;Fukuda, K
研究目的：目前有报道称骨髓（BM）细胞可能参与某些全身血管疾病的重塑；然而，BM细胞是否参与肺动脉血管重塑和肺动脉高压（PH）的进展仍不清楚。本研究的目的是探讨BM来源的细胞是否有助于缺氧诱导的PH中的肺血管重塑。 材料和方法：为了研究BM来源的细胞的作用，我们将增强型绿色荧光蛋白（GFP）转基因小鼠的整个BM移植到致死照射的同系小鼠（n = 30）中。 S周后，嵌合体小鼠使用低氧室（10％O-2）暴露于持续缺氧长达4或8周（每组10只小鼠）。测量血流动力学和右心室 (RV) 重量与左心室 (LV) 重量之比 RV/(LV + 隔膜 [S]) 后，进行组织学和免疫荧光染色。 结果：BM 移植小鼠表现出高度嵌合性（平均 [+/- SEM]，91 +/- 2.3%）。 PH 小鼠的 RV 收缩压和 RV/(LV + S) 比率随时间显着增加，表明 RV 肥大。在 PH 小鼠的肺动脉中观察到明显的血管重塑，包括内侧肥大和外膜增殖。引人注目的是，在缺氧诱导的 PH 小鼠中，在肺动脉壁（包括外膜）处观察到大量 GFP(+) 细胞，而在对照小鼠中观察到的细胞很少。使用共焦激光扫描显微镜进行的 Metaspectrometer 测量证实，这种绿色荧光是由 GFP 产生的，表明这些 GFP(+) 细胞是从 BM 中动员出来的。它们中的大多数表达α-平滑肌肌动蛋白、一种平滑肌细胞或肌成纤维细胞表型，并有助于肺血管重塑。 GFP基因的半定量聚合酶链反应显示，在PH组中观察到的BM来源的GFP阳性细胞是对照小鼠的八倍以上。结论：BM来源的细胞动员到高血压肺动脉，并有助于缺氧诱导的PH小鼠的肺血管重塑。
Study objective: in these days, it was reported that bone marrow (BM) cells might take part in the remodeling of some systemic vascular diseases; however, it remains unknown whether the BM cells were involved in the vascular remodeling of pulmonary arteries and the progression of pulmonary hypertension (PH). The purpose of this study was to investigate whether BM-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced PH.Materials and methods: To investigate the role of BM-derived cells, we transplanted the whole BM of enhanced green fluorescent protein (GFP)-transgenic mice to the lethally irradiated syngeneic mice (n = 30). After S weeks, chimera mice were exposed to consistent hypoxia using a hypoxic chamber (10% O-2) for up to 4 or 8 weeks (10 mice per group). After hemodynamics and the ratio of right ventricular (RV) weight to left ventricle (LV) weight, RV/(LV + septum [S]), were measured, histologic and immunofluorescent staining were performed.Results: BM-transplanted mice showed a high chimerism (mean [+/- SEM], 91 +/- 2.3%). RV systolic pressure and the RV/(LV + S) ratio increased significantly with time in PH mice, indicating RV hypertrophy. Marked vascular remodeling including medial hypertrophy and adventitial proliferation was observed in the pulmonary arteries of PH mice. Strikingly, a number of GFP(+) cells were observed at the pulmonary arterial wall, including the adventitia, in hypoxia-induced PH mice, while very few cells were observed in the control mice. Metaspectrometer measurements using confocal laser scanning microscopy confirmed that this green fluorescence was produced by GFP, suggesting that these GFP(+) cells were mobilized from the BM. Most of them expressed alpha-smooth muscle actin, a smooth muscle cell, or myofibroblast phenotype, and contributed to the pulmonary vascular remodeling. A semiquantitative polymerase chain reaction of the GFP gene revealed that the BM-derived GFP-positive cells in the PH group were observed more than eightfold as often compared with the control mice.Conclusion: The BM-derived cells mobilize to the hypertensive pulmonary arteries and contribute to the pulmonary vascular remodeling in hypoxia-induced PH mice.