Signals for Post-pneumonectomy Compensatory Lung Growth

全肺切除术后代偿性肺生长的信号

• 批准号: 8042764
• 负责人: Connie C. W. Hsia
• 金额: $ 44.77万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8042764
• 关键词: Adult; Affect; Alveolar; Apoptosis; Blood Vessel Tissue; Blood Volume; Blood capillaries; Canis familiaris; Cell Differentiation process; Cell Proliferation; Cells; Chronic lung disease; Clinical; Coculture Techniques; Endothelial Cells; Epithelial; Epithelial Cells; Erythropoietin; Erythropoietin Receptor; Event; Excision; Exercise; Financial compensation; Goals; Growth; Growth Factor; Heterogeneity; High Resolution Computed Tomography; Human; Hypoxia Inducible Factor; Image; In Vitro; Intervention; Knowledge; Left; Liquid substance; Lobar; Lobe; Lung; Lung diseases; Measures; Mechanical Stress; Mechanics; Mediator of activation protein; Microspheres; Modeling; Molecular; Natural regeneration; Pathway interactions; Perfusion; Play; Pneumonectomy; Prosthesis; Pulmonary artery structure; Radial; Regional Perfusion; Regulatory Pathway; Residual state; Respiratory physiology; Response to stimulus physiology; Right lung; Role; Sampling; Signal Transduction; Silicones; Stimulus; Stress; Stretching; Structure; Structure of parenchyma of lung; Supplementation; Testing; Time; Tissues; Tretinoin; Vascular Endothelial Growth Factors; angiogenesis; biological adaptation to stress; capillary; cell growth; cell type; improved; in vivo; morphometry; paracrine; pressure; prevent; promoter; recombinant human erythropoietin; response; shear stress

DESCRIPTION (provided by applicant): In adult dogs after pneumonectomy (PNX), mechanical forces on the remaining lung are thought to stimulate compensatory lung growth. Following moderate (42% of total) resection, lobar growth is non-uniform. As resection increases (58-70%), alveolar growth is stimulated in all remaining lobes probably due to mechanical forces exceeding a threshold for cellular stimulation. Supplementation with all trans-retinoic acid (RA), a promoter of cell growth and differentiation, enhanced some aspects of alveolar-capillary response following 58% but not 42% resection, suggesting a relationship between the intensity of endogenous stimuli and the capacity for pharmacological growth enhancement. Lobar expansion explains ~40-70% of post-PNX compensation, presumably via increased septal strain/shear; residual compensation might be explained by elevated lobar perfusion via increased strain/shear on alveolar capillaries. Lobar expansion may also alter and interact with regional perfusion. Relationship of in vivo tissue mechanical stress to cellular response has not been established, but the hypoxia-inducible factor-erythropoietin-vascular endothelial growth factor (HIF-EPO- VEGF) axis is implicated. Our hypotheses are: 1) Regional compensatory lung growth varies directly with the intensity of regional mechanical stimuli, and 2) Growth factor supplementation amplifies natural response to post-PNX mechanical stimuli, but cannot initiate de novo compensatory lung growth in the absence of sufficient endogenous stimuli. In Aim 1, we will quantify post-PNX regional lung strain and shear using bronchovascular landmarks imaged at different transpulmonary pressures by high resolution computed tomography (HRCT) and correlate strain/shear with regional cellular response in HIF-EPO-VEGF axis. In Aim 2, we will test the effects of altering lobar perfusion on post-PNX compensation by banding one lobar pulmonary artery, which restrict its perfusion while exaggerating post-PNX perfusion to unbanded lobes. Regional perfusion will be measured by fluorescent microspheres. The remaining lobes will be assessed for cell signaling and for alveolar ultrastructure by morphometry. In Aim 3, we will establish cause-effect mechanisms of mechanical stresses on growth- related signaling in vitro using cultured lung epithelial cells subjected to mechanical strain and endothelial cells subjected to strain and fluid shear. Mechano-stress response of HIF-EPO-VEGF axis will be compared to its O2-sensitive response. In vitro signaling events will be related to parallel in vivo stress response. Epithelial- endothelial co-cultures will test for diffusible mediators of mechanotransduction. In Aim 4, we will amplify EPO/EPO-R signaling post-PNX by nebulization of recombinant human erythropoietin (rhEPO) to determine its local effect on angiogenesis, growth and function in relation to in vivo regional mechanical stresses. These studies define fundamental mechanical stimuli-response relationships in a robust model of compensatory lung growth, and explore a potential intervention for augmenting the endogenous response. Results have important basic and clinical implications for the re-initiation of lung growth in human chronic lung disease. PUBLIC HEALTH RELEVANCE: When one lung is surgically removed, the remaining lung undergoes compensatory growth where more lung tissue is generated to improve lung function. Our goal is to understand the stimuli and regulatory pathways responsible for re-initiating growth in the adult lung, specifically those pathways related to mechanical forces that stretch and distort the remaining tissue and blood vessels. We will study the intact lung as well as lung cells grown in culture subjected to mechanical distortion. These studies will advance fundamental knowledge of lung regeneration, and explore a potential intervention for augmenting the natural response. The results have important implications for the stimulation of lung re-growth in the treatment of human lung disease.

描述（由申请方提供）：在肺切除术（PNX）后的成年犬中，认为剩余肺上的机械力刺激了代偿性肺生长。在中度（总切除量的42%）切除后，肺叶生长不均匀。随着切除增加（58-70%），可能由于机械力超过细胞刺激阈值，所有剩余肺叶中的肺泡生长受到刺激。补充所有的反式维甲酸（RA），促进细胞生长和分化，增强肺泡毛细血管反应的某些方面后58%，但不是42%切除，这表明内源性刺激的强度和药理学生长增强的能力之间的关系。肺叶扩张解释了约40-70%的PNX后补偿，推测是通过增加间隔应变/剪切力;剩余补偿可能是通过肺泡毛细血管上的应变/剪切力增加导致肺叶灌注升高来解释的。肺叶扩张也可能改变局部灌注并与其相互作用。体内组织机械应力与细胞反应的关系尚未建立，但涉及缺氧诱导因子-促红细胞生成素-血管内皮生长因子（HIF-EPO- VEGF）轴。我们的假设是：1）局部代偿性肺生长直接随局部机械刺激的强度而变化，和2）生长因子补充增强了对PNX后机械刺激的自然反应，但在缺乏足够的内源性刺激的情况下不能启动从头代偿性肺生长。在目标1中，我们将使用高分辨率计算机断层扫描（HRCT）在不同经肺动脉压下成像的支气管血管标志量化PNX后局部肺应变和剪切，并将应变/剪切与HIF-EPO-VEGF轴中的局部细胞反应相关联。在目标2中，我们将测试改变肺叶灌注对PNX后补偿的影响，方法是将一个肺叶肺动脉捆扎，限制其灌注，同时将PNX后灌注扩大到未捆扎的肺叶。将通过荧光微球测量局部灌注。将通过形态测定法评估剩余肺叶的细胞信号传导和肺泡超微结构。在目标3中，我们将使用经受机械应变的培养的肺上皮细胞和经受应变和流体剪切的内皮细胞在体外建立机械应力对生长相关信号传导的因果机制。将HIF-EPO-VEGF轴的机械应激反应与其O2敏感性反应进行比较。体外信号传导事件将与平行的体内应激反应相关。上皮-内皮共培养物将测试机械转导的可扩散介质。在目的4中，我们将通过雾化重组人促红细胞生成素（rhEPO）来扩增PNX后的EPO/EPO-R信号传导，以确定其对血管生成、生长和与体内区域机械应力相关的功能的局部作用。这些研究定义了一个强大的代偿性肺生长模型中的基本机械刺激-反应关系，并探索了一种增强内源性反应的潜在干预措施。这些结果对于人类慢性肺病中肺生长的重新启动具有重要的基础和临床意义。 公共卫生关系：当一个肺被手术切除时，剩余的肺经历代偿性生长，其中产生更多的肺组织以改善肺功能。我们的目标是了解负责重新启动成人肺生长的刺激和调节途径，特别是那些与拉伸和扭曲剩余组织和血管的机械力相关的途径。我们将研究完整的肺以及在受到机械变形的培养物中生长的肺细胞。这些研究将推进肺再生的基础知识，并探索增强自然反应的潜在干预措施。这些结果对于刺激肺再生治疗人类肺部疾病具有重要意义。