Non-Resident Lung angiogenic precursor cells in bronchopulmonary dysplasia

支气管肺发育不良中的非驻留肺血管生成前体细胞

• 批准号: 8040938
• 负责人: Vivek Balasubramaniam
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8040938
• 关键词: Adolescence; Adult; Adverse effects; Affect; Alveolar; Animals; Asthma; Blood Circulation; Blood Vessels; Bone Marrow; Bone Marrow Cells; Bronchopulmonary Dysplasia; CD34 gene; Cardiovascular system; Cell Count; Cell surface; Cells; Child; Chronic Obstructive Airway Disease; Chronic lung disease; Data; Development; Endothelial Cells; Engraftment; Environmental air flow; Evolution; Exercise; Exposure to; Gases; Goals; Growth; Growth and Development function; Healed; Hematopoietic; Homing; Hyperoxia; In Vitro; Incidence; Infant; Injury; Kidney; Lead; Lung; Maintenance; Modeling; Mus; Neonatal; Nitric Oxide; Oxygen; PTPRC gene; Play; Population; Premature Birth; Premature Infant; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Recovery; Rodent; Role; Secondary to; Signal Transduction; Site; Source; Stem cells; Structure; Techniques; Therapeutic; Therapeutic Intervention; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Work; antiangiogenesis therapy; base; cell growth; critical period; cytokine; density; emerging adult; healing; high risk; human NOS3 protein; improved; infancy; injured; injury and repair; lung development; lung injury; lung preservation; mortality; mouse model; neonatal exposure; neonatal lung injury; neonate; novel; novel therapeutic intervention; oxygen toxicity; precursor cell; receptor; repaired; response to injury; vasculogenesis

DESCRIPTION (provided by applicant): Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy that is the result of premature birth. Infants with BPD have abnormal lung structure that is characterized by reduced pulmonary vascular density and a dysmorphic vascular structure. This results in impaired gas exchange, exercise intolerance, pulmonary hypertension, an increased incidence of asthma and early mortality. The mechanisms that impair lung development are poorly understood and there are few therapeutic interventions in the treatment of BPD. Recently, circulating angiogenic or endothelial progenitor cells (EPC) have been identified and characterized. These EPCs are believed to play a role in the recovery of blood vessels after injury. The role of EPCs during normal lung vascular and alveolar growth is unknown. In addition, the role these cells play in the neonate during the recovery from lung injury is unknown. Our goal is to characterize the role of EPCs in lung growth and development and determine if these cells are able to play a role in lung vascular and alveolar growth during and in recovery after lung injury. We propose the following hypothesis that a reduction in the mobilization, engraftment and survival of non- resident lung endothelial precursor cells (EPCs), is a mechanism contributing to impaired lung vascular and alveolar growth during and after exposure to neonatal hyperoxia. In order to study this hypothesis we are proposing the following specific aims in a mouse model: 1) To determine the therapeutic role of exogenous EPCs in the maintenance of lung vascular and alveolar growth during exposure to, and in the recovery from, neonatal moderate hyperoxia. 2) To determine if non-resident lung bone marrow derived cells participate in the preservation of lung structure during moderate hyperoxia exposure of adult mice. 3) To study, in vitro, the mechanisms by which VEGF, Epo, NO and hyperoxia affect EPC growth and function. PROJECT NARRATIVE: We expect that the results of this study will provide a better understanding of the roles and mechanisms by which extrinsic (circulating) cells and intrinsic (resident lung) cells play in lung vascular and alveolar growth, especially during and in the recovery from neonatal lung injury. A better understanding of these mechanisms of neonatal lung injury and repair may lead to novel therapies in the treatment of BPD.

描述(申请人提供)：支气管肺发育不良(BPD)是一种婴儿时期的慢性肺部疾病，是早产的结果。BPD患儿肺结构异常，以肺血管密度降低和血管结构畸形为特征。这会导致气体交换受损、运动不耐受、肺动脉高压、哮喘发病率增加和早期死亡。损害肺发育的机制知之甚少，治疗BPD的治疗干预措施也很少。最近，循环中的血管生成或内皮祖细胞(EPC)已被鉴定和鉴定。这些内皮祖细胞被认为在损伤后血管的恢复中发挥作用。内皮祖细胞在正常肺血管和肺泡生长过程中的作用尚不清楚。此外，这些细胞在新生儿肺损伤恢复过程中扮演的角色尚不清楚。我们的目标是确定内皮祖细胞在肺生长和发育中的作用，并确定这些细胞在肺损伤期间和恢复过程中是否能够在肺血管和肺泡生长中发挥作用。我们提出以下假设：非常驻肺内皮前体细胞(EPC)的动员、植入和存活的减少是导致新生儿高氧暴露期间和之后肺血管和肺泡生长受损的机制之一。为了研究这一假说，我们在小鼠模型中提出了以下具体目标：1)确定外源性内皮祖细胞在新生儿中度高氧暴露和恢复期间维持肺血管和肺泡生长的治疗作用。2)探讨非居民肺骨髓来源细胞是否参与了中度高氧暴露对小鼠肺结构的保护作用。3)体外研究血管内皮生长因子、促红细胞生成素、一氧化氮和高氧对血管内皮细胞生长和功能的影响机制。项目简介：我们期望这项研究的结果能够更好地理解外源性(循环)细胞和内源性(常驻)细胞在肺血管和肺泡生长中的作用和机制，特别是在新生儿肺损伤的恢复过程中。更好地了解新生儿肺损伤和修复的这些机制可能会导致治疗BPD的新疗法。