Circulating Fibrocytes in Hyperoxic Lung Vascular Remodeling

许多BPD患儿的肺微血管发育和肺动脉(PA)异常 观察到了结构重塑。后一过程包括耐药PA的异常肌化 肺外周可见肺内膜肥大、外膜增厚和纤维化。 BPD肺血管发育异常和结构重构的原因尚不清楚。 明白了。长期以来，人们一直认为增厚的PA中扩大的细胞群起源于 通过常驻肺成纤维细胞和平滑肌细胞(SMC)的增殖以及通过分化 常驻肺成纤维细胞转化为肌成纤维细胞。然而，新的实验证据表明，一名非居民 组织间充质细胞(成纤维细胞、肌成纤维细胞、SMC)来源。在不同类型的 间充质祖细胞是一种循环中的白细胞亚群，称为纤维细胞。 作为愈合创面结构组织重塑和纤维化的主要贡献者，博莱霉素诱导的 肺损伤和哮喘。我们最近证实了慢性阻塞性肺疾病患者纤维细胞中PA的强阳性积聚。 结果表明，这些循环细胞对新生儿低氧性肺动脉高压的形成至关重要。 在那个环境下可以看到肺血管结构重塑。我们的初步数据显示，循环中 纤维细胞也有助于新生大鼠和小鼠暴露于 高氧血症(BPD动物模型)。初步数据支持氧化剂失衡和内皮素在糖尿病中的作用 纤维细胞在肺中的募集。因此，我们建议测试总体假设，即在 在高氧性肺损伤的背景下，循环中的纤维细胞被招募到肺中，在那里它们扮演着 间充质细胞的前体细胞，并在肺血管重塑和 EC-SOD和ET-1在这一过程中起关键作用。我们将确定 纤维细胞向肺和肺血管系统募集的机制及其作用 使用药物策略和遗传模型来重塑以操纵表达 可能与纤维细胞募集和分化有关的分子。这些实验将导致 更好地了解BPD的血管变化，并最终在选择性治疗的发展中 减少高氧肺循环间充质祖细胞募集的策略 患有BPD的人类婴儿。

In many infants with BPD abnormal pulmonary microvascular development and pulmonary artery (PA) structural remodeling are observed. The latter process includes abnormal muscularization of resistance PA in the lung periphery, as well as medial hypertrophy, adventitial thickening and fibrosis in more proximal PA. The causes of abnormal pulmonary vascular development and structural remodeling in BPD are poorly understood. It has long been assumed that the expanded population of cells in the thickened PA originates via proliferation of resident lung fibroblasts and smooth muscle cells (SMC), as well as via differentiation of resident lung fibroblasts into myofibroblasts. However, new experimental evidence suggests a non-resident source for tissue mesenchymal cells (fibroblasts, myofibroblasts, SMC). Among different types of mesenchymal progenitors, a subpopulation of circulating leukocytes, termed fibrocytes, has been proposed as a major contributor to the structural tissue remodeling and fibrosis in healing wounds, bleomycin-induced lung injury, and asthma. We have recently demonstrated the robust PA accumulation of fibrocytes in chronic hypoxic neonatal pulmonary hypertension and showed that these circulating cells are crucial for the pulmonary vascular structural remodeling seen in that setting. Our preliminary data suggest that circulating fibrocytes also contribute to the vascular remodeling observed in neonatal rats and mice exposed to hyperoxia (animal models of BPD). Preliminary data support a role for oxidant imbalances and endothelin in the recruitment of fibrocytes to the lung. We therefore propose to test the overall hypothesis that, in the setting of hyperoxia-induced lung injury, circulating fibrocytes are recruited to the lung where they act as progenitors of mesenchymal cells, and contribute significantly to pulmonary vascular remodeling and pulmonary hypertension, and that EC-SOD and ET-1 play critical roles in this process. We will determine the mechanisms involved in the recruitment of fibrocytes to the lung and lung vasculature and their contribution to remodeling using both pharmacologic strategies and genetic models to manipulate expression of molecules potentially involved in fibrocyte recruitment and differentiation. These experiments will result in a better understanding of vascular changes in BPD and, ultimately in the development of selective therapeutic strategies to decrease the recruitment of circulating mesenchymal progenitors to the hyperoxic lung in human infants with BPD.