Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.
Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.
复制标题
DOI：
10.1038/nm.4035
复制
发表时间：
2016-02
期刊：
影响因子：
82.9
通讯作者：
Ding BS
中科院分区：
文献类型：
--
作者：
Cao Z;Lis R;Ginsberg M;Chavez D;Shido K;Rabbany SY;Fong GH;Sakmar TP;Rafii S;Ding BS
虽然肺可以在损伤后进行自我修复，但慢性损伤或患病肺中的纤维化可能以再生为代价而发生。在这里，我们研究造血血管龛如何调节肺泡修复和肺纤维化。通过对小鼠肺内注射博莱霉素或盐酸，我们发现重复性肺损伤激活了肺毛细血管内皮细胞（PCECs）和血管周围巨噬细胞，阻碍了肺泡修复并促进了纤维化。尽管PCEC上表达的趋化因子受体CXCR 7在用博来霉素或盐酸单轮治疗后起到预防上皮损伤和改善纤维化的作用，但重复损伤导致CXCR 7表达的抑制和表达血管内皮生长因子受体1（VEGFR 1）的血管周围巨噬细胞的募集。这种募集刺激PCEC中Notch配体Jagged 1（由Jag 1编码）的Wnt/β-连环蛋白依赖性持续上调，这反过来刺激血管周围成纤维细胞中旺盛的Notch信号传导并增强纤维化。肺损伤后给予CXCR 7激动剂或PCEC靶向Jag 1 shRNA可促进肺泡修复并减少纤维化。因此，靶向适应不良的造血-血管生态位，其中巨噬细胞、PCEC和血管周围成纤维细胞相互作用，可能有助于开发刺激肺再生和减轻纤维化的疗法。
Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladaptbed hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.