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: 8586898
• 负责人: Connie C. W. Hsia
• 金额: $ 43.14万
• 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 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586898
• 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; 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; lung regeneration; 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.

项目摘要/摘要 在成年狗的全肺切除术(PNX)后，机械压力被认为是刺激剩余肺 代偿性肺生长。中度切除(占总切除的42%)后，肺叶生长不均匀。AS 切除增加(58-70%)，所有剩余肺叶的肺泡生长被刺激，可能是由于机械 超过细胞刺激阈值的力量。补充全反式维甲酸(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 58%，而不是42%，这表明内源性刺激的强度与 药理生长促进能力。肺叶扩张可解释PNX后约40%-70%的病例 补偿，可能是通过增加间隔应变/剪切；剩余补偿可以用以下方式解释 肺泡毛细血管张力/剪切力增加导致肺叶血流灌注增加。大叶扩张也可能改变和 与区域血流灌注相互作用。体内组织机械应力与细胞反应的关系尚未见报道 但缺氧诱导因子-促红细胞生成素-血管内皮生长因子(HIF-EPO-HIF-EPO- 血管内皮生长因子)轴被牵连。我们的假设是：1)区域代偿性肺生长与年龄成正比 局部机械刺激的强度，以及2)补充生长因子放大对 PNX后机械刺激，但不能在缺乏足够的 内源性刺激。在目标1中，我们将使用支气管血管来量化pnx术后的局部肺应变和切变。 高分辨率计算机断层扫描(HRCT)在不同经肺压力下成像的标志物 HIF-EPO-VEGF轴的应变/剪切与局部细胞反应相关。在目标2中，我们将测试这些效果 通过结扎单侧肺叶动脉改变肺血流灌注对PNX术后代偿的影响 血流灌注，同时夸大PNX术后对未捆绑的肺叶的血流灌注。区域血流灌注将通过以下方式测量 荧光微球。将对剩余的肺叶进行细胞信号和肺泡超微结构的评估。 通过形态计量学。在目标3中，我们将建立机械应力对生长的因果机制- 机械张力作用下培养的肺上皮细胞和内皮细胞的体外相关信号 承受应变和流体剪切。HIF-EPO-VEGF轴的机械应力反应将与其 对O2敏感的反应。体外信号事件将与体内平行的应激反应有关。上皮性- 内皮细胞共培养将测试机械转导的可扩散介质。在目标4中，我们将放大 雾化吸入重组人促红细胞生成素检测PNX后EPO/EPO-R信号转导 与体内局部机械应力有关的局部对血管生成、生长和功能的影响。这些 研究确定了一个稳健的代偿性肺模型中的基本机械刺激-反应关系 并探索一种潜在的干预措施，以增强内源性反应。结果具有重要的意义 人类慢性肺病患者重新启动肺生长的基础和临床意义。

项目成果

What can imaging tell us about physiology? Lung growth and regional mechanical strain.

影像学可以告诉我们什么生理学信息？

• DOI: 10.1152/japplphysiol.00289.2012
• 发表时间: 2012
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Hsia,ConnieCW;Tawhai,MerrynH
• 通讯作者: Tawhai,MerrynH

Polymeric nanoparticles for pulmonary protein and DNA delivery.

• DOI: 10.1016/j.actbio.2014.01.033
• 发表时间: 2014-06
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: Menon JU;Ravikumar P;Pise A;Gyawali D;Hsia CC;Nguyen KT
• 通讯作者: Nguyen KT

Nanoparticle facilitated inhalational delivery of erythropoietin receptor cDNA protects against hyperoxic lung injury.

• DOI: 10.1016/j.nano.2015.10.004
• 发表时间: 2016-04
• 期刊: Nanomedicine : nanotechnology, biology, and medicine
• 作者: Ravikumar P;Menon JU;Punnakitikashem P;Gyawali D;Togao O;Takahashi M;Zhang J;Ye J;Moe OW;Nguyen KT;Hsia CCW
• 通讯作者: Hsia CCW

Source of error on A-aDO2 calculated from blood stored in plastic and glass syringes.

根据塑料和玻璃注射器中储存的血液计算得出的 A-aDO2 的误差来源。

• DOI: 10.1152/jappl.1997.82.1.196
• 发表时间: 1997
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Wu,EY;Barazanji,KW;JohnsonJr,RL
• 通讯作者: JohnsonJr,RL

αKlotho deficiency in acute kidney injury contributes to lung damage.

急性肾损伤时αKlotho 缺乏会导致肺损伤。

• DOI: 10.1152/japplphysiol.00792.2015
• 发表时间: 2016
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Ravikumar,Priya;Li,Liping;Ye,Jianfeng;Shi,Mingjun;Taniguchi,Masatomo;Zhang,Jianning;Kuro-o,Makoto;Hu,MingChang;Moe,OrsonW;Hsia,ConnieCW
• 通讯作者: Hsia,ConnieCW