Inhibition of the SDF-1/CXCR4 axis attenuates neonatal hypoxia-induced pulmonary hypertension.
Inhibition of the SDF-1/CXCR4 axis attenuates neonatal hypoxia-induced pulmonary hypertension.
复制标题
DOI：
10.1161/circresaha.109.197533
复制
发表时间：
2009-06-05
影响因子：
20.1
通讯作者：
Hare JM
中科院分区：
文献类型：
--
作者：
Young KC;Torres E;Hatzistergos KE;Hehre D;Suguihara C;Hare JM
新生儿肺暴露于慢性缺氧会产生显著的肺血管重塑、右心室肥大（RVH）和肺泡化减少。鉴于最近的数据表明，干细胞可能有助于肺血管重塑和RVH，我们测试的假设，即阻断基质衍生因子-1（SDF-1），一个关键的干细胞动员剂或其受体，趋化因子受体4（CXCR 4），将减弱和逆转缺氧诱导的新生小鼠心肺重塑。将暴露于常氧或缺氧的新生小鼠随机分配，从出生后第1-7天（预防策略）或出生后第7-14天（治疗策略）每天腹膜内注射生理盐水（PL）、AMD 3100或抗SDF-1抗体。与PL相比，SDF-1/CXCR 4轴的抑制显著改善肺泡化，以及降低肺动脉高压、RVH、血管重塑、血管细胞增殖和肺或RV干细胞表达至接近基线值。因此，我们得出结论，SDF-1/CXCR 4轴通过减少祖细胞向肺血管的募集以及减少肺血管细胞增殖来预防和逆转新生小鼠缺氧诱导的心肺重塑。这些数据为SDF-1/CXCR 4轴在新生儿缺氧诱导的心肺重构发病机制中的作用提供了新的见解，并具有重要的治疗意义。
Exposure of the neonatal lung to chronic hypoxia produces significant pulmonary vascular remodeling, right ventricular hypertrophy (RVH), and decreased lung alveolarization. Given recent data suggesting that stem cells could contribute to pulmonary vascular remodeling and RVH, we tested the hypothesis that blockade of stromal derived factor-1 (SDF-1), a key stem cell mobilizer or its receptor, chemokine receptor 4 (CXCR4), would attenuate and reverse hypoxia-induced cardiopulmonary remodeling in newborn mice. Neonatal mice exposed to normoxia or hypoxia were randomly assigned to receive daily intra-peritoneal injections of normal saline (PL), AMD3100, or anti-SDF-1 antibody from postnatal day 1–7 (preventative strategy) or postnatal day 7–14 (therapeutic strategy). As compared to PL, inhibition of the SDF-1/CXCR4 axis significantly improved lung alveolarization, as well as decreased pulmonary hypertension, RVH, vascular remodeling, vascular cell proliferation and lung or RV stem cell expressions to near baseline values. We therefore conclude that the SDF-1/CXCR4 axis both prevents and reverses hypoxia-induced cardiopulmonary remodeling in neonatal mice, by decreasing progenitor cell recruitment to the pulmonary vasculature as well as by decreasing pulmonary vascular cell proliferation. These data offer novel insights into the role of the SDF-1/CXCR4 axis in the pathogenesis of neonatal hypoxia-induced cardiopulmonary remodeling and have important therapeutic implications.