Circulating Fibrocytes in Hyperoxic Lung Vascular Remodeling

高氧肺血管重塑中的循环纤维细胞

• 批准号: 7700593
• 负责人: Kurt R. Stenmark
• 金额: $ 34.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7700593
• 关键词: Affect; Ally; Alveolar; Alveolus; Animal Model; Animals; Appearance; Area; Asthma; Birth; Bleomycin; Blood Vessels; Bronchopulmonary Dysplasia; Cells; Chronic; Chronic lung disease; Collagen; Complication; Data; Deposition; Development; Endothelin; Endothelin-1; Fibroblasts; Fibronectins; Fibrosis; Genetic Models; Goals; Human; Hyperoxia; Hypertrophy; Hypoxia; Infant; Inflammatory; Inflammatory Response; Knock-out; Leukocytes; Lung; Lung Inflammation; Medial; Mediating; Mesenchymal; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Mus; Myofibroblast; Neonatal; Numbers; Oxidants; Oxygen Therapy Care; Play; Population; Process; Production; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Recruitment Activity; Research Personnel; Resistance; Respiratory distress; Risk; Rodent; Role; Small Interfering RNA; Smooth Muscle Myocytes; Source; Stem cells; Stress; Superoxide Dismutase; Testing; Therapeutic; Time; Tissues; Vascular Diseases; Vascular remodeling; Ventilator; Work; Wound Healing; attenuation; chemokine; chemokine receptor; clinically significant; cytokine; extracellular; improved; in vivo; lung development; lung injury; neonatal pulmonary hypertension; novel; prevent; progenitor; programs; receptor; research study; response; tool

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.

在许多患有 BPD 的婴儿中，肺微血管发育和肺动脉 (PA) 异常 观察到结构重塑。后一过程包括抵抗 PA 的异常肌肉化 肺周围有肺内肥厚、外膜增厚和纤维化。 BPD 中肺血管异常发育和结构重塑的原因尚不清楚 明白了。长期以来，人们一直认为增厚的 PA 中细胞数量的增加源自 通过常驻肺成纤维细胞和平滑肌细胞 (SMC) 的增殖，以及通过 常驻肺成纤维细胞转变为肌成纤维细胞。然而，新的实验证据表明非居民 组织间充质细胞（成纤维细胞、肌成纤维细胞、SMC）的来源。不同类型之中 间充质祖细胞是循环白细胞的一个亚群，称为纤维细胞，已被提出 作为伤口愈合过程中结构组织重塑和纤维化的主要贡献者，博来霉素诱导的 肺损伤和哮喘。我们最近证明了慢性病中纤维细胞的强效 PA 积累 缺氧新生儿肺动脉高压，并表明这些循环细胞对于新生儿肺动脉高压至关重要 在这种情况下观察到肺血管结构重塑。我们的初步数据表明，流通 纤维细胞还有助于在新生大鼠和小鼠中观察到的血管重塑 高氧症（BPD 动物模型）。初步数据支持氧化剂失衡和内皮素在 纤维细胞募集到肺部。因此，我们建议检验总体假设，即 在高氧引起的肺损伤的情况下，循环纤维细胞被募集到肺部，在那里它们充当 间充质细胞的祖细胞，对肺血管重塑和 肺动脉高压，EC-SOD 和 ET-1 在此过程中发挥着关键作用。我们将确定 纤维细胞募集至肺和肺血管系统的机制及其贡献 使用药理学策略和遗传模型进行重塑以操纵表达 可能参与纤维细胞募集和分化的分子。这些实验将导致 更好地了解 BPD 的血管变化，并最终开发选择性治疗方法 减少循环间充质祖细胞向高氧肺募集的策略 患有 BPD 的人类婴儿。