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: 8383489
• 负责人: Connie C. W. Hsia
• 金额: $ 40.55万
• 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/8383489
• 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; abstracting; angiogenesis; biological adaptation to stress; capillary; cell growth; cell type; improved; in vivo; morphometry; paracrine; pressure; prevent; promoter; recombinant human erythropoietin; response; shear stress

Project Summary / Abstract 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.

项目总结/摘要 在肺切除术（PNX）后的成年犬中，对剩余肺的机械力被认为是刺激 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。作为 切除率增加（58-70%），可能由于机械性刺激，所有剩余肺叶的肺泡生长受到刺激。 超过细胞刺激阈值的力。补充全反式维甲酸（RA）， 细胞生长和分化的促进剂，增强肺泡毛细血管反应的某些方面， 58%而不是42%切除，表明内源性刺激的强度与肿瘤的生长之间的关系。 药理学生长增强的能力。肺叶扩张可解释约40-70%的PNX后 补偿，可能是通过增加间隔应变/剪切;剩余补偿可能解释为 通过肺泡毛细血管上的应变/剪切力增加而增加肺叶灌注。肺叶扩张也可能改变， 与局部灌注相互作用。体内组织机械应力与细胞反应的关系尚未得到证实。 低氧诱导因子促红细胞生成素-血管内皮生长因子（HIF-EPO-VEGF）是一种重要的促红细胞生成素。 VEGF）轴有牵连。我们的假设是：（1）区域代偿性肺生长直接随 区域机械刺激的强度，和2）生长因子补充放大自然反应， PNX后的机械刺激，但不能启动从头代偿性肺生长，在缺乏足够的 内源性刺激在目标1中，我们将使用支气管血管成像技术量化PNX后局部肺应变和剪切力。 通过高分辨率计算机断层扫描（HRCT）在不同经颅压下成像的标志， 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 通过结扎一根肺叶肺动脉来改变PNX后补偿的肺叶灌注，从而限制其血流 灌注，同时将PNX后灌注扩大到未带状叶。将通过以下方法测量局部灌注： 荧光微球。将对其余肺叶进行细胞信号传导和肺泡超微结构评估 通过形态测定法。在目标3中，我们将建立机械应力对生长的因果机制- 使用经受机械应变的培养的肺上皮细胞和内皮细胞的体外相关信号传导 受到应变和流体剪切。将HIF-EPO-VEGF轴的机械应激反应与其自身的机械应激反应进行比较。 氧气敏感反应。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传导的可扩散介质。在目标4中，我们将扩大 通过雾化重组人促红细胞生成素（rhEPO）来检测PNX后EPO/EPO-R信号传导，以确定其 与体内局部机械应力有关的对血管生成、生长和功能的局部影响。这些 研究确定了代偿性肺的稳健模型中的基本机械刺激-反应关系 生长，并探索一种潜在的干预措施，以增强内源性反应。结果有重要 人类慢性肺病中肺生长重新启动的基础和临床意义。