Structural Plasticity in Compensatory Lung Growth and Remodeling

代偿性肺生长和重塑中的结构可塑性

• 批准号: 9263555
• 负责人: Connie C. W. Hsia
• 金额: $ 70.57万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263555
• 关键词: Acinus organ component; Address; Adult; Alveolar; Anatomy; Angiogenic Factor; Architecture; Biomedical Engineering; Blood capillaries; Blood gas; Breathing; Canis familiaris; Child; Complementary DNA; Congenital diaphragmatic hernia; Cytoprotection; Diffusion; Disease; Elastases; Electron Microscopy; Equilibrium; Erythropoietin; Erythropoietin Receptor; Etiology; Excision; Exhibits; Fibrosis; Financial compensation; Gases; Genetic; Goals; Growth; Imaging Techniques; Impairment; In Vitro; Inflammatory; Intervention; Lobe; Lung; Lung diseases; Mechanical Stress; Mechanics; Mediating; Modeling; Mus; Nanotechnology; Natural regeneration; Operative Surgical Procedures; Outcome; Oxidants; Oxidative Stress; Pathology; Pathway interactions; Perfusion; Pharmacology; Plasticizers; Pneumonectomy; Pulmonary Emphysema; Recruitment Activity; Regenerative Medicine; Regenerative response; Reporting; Respiratory physiology; Response to stimulus physiology; Signal Transduction; Stem cells; Stimulus; Structure; Supplementation; Testing; Thinness; Time; Tissues; Translations; Transplantation; Tretinoin; angiogenesis; capillary; cell growth; experience; factor A; functional gain; functional outcomes; improved; improved functioning; in vivo; lung regeneration; mechanical force; microCT; nanoparticle; novel; oxidant stress; oxidation; paracrine; promoter; receptor; regenerative; repaired; response; success; treatment strategy; uptake; young adult

Project Summary Following loss of ~58% of lung units by right pneumonectomy (PNX) in adult canines, supra-threshold tissue and microvascular mechanical stress additively stimulate compensatory lung growth and remodeling (CLGR) of remaining lung units, leading to regeneration of alveolar tissue-capillaries and restoring ~50% of the lost function. This robust model of regeneration mimics the consequences of destructive lung disease, allowing exploration of adaptive mechanisms in the remaining functioning lung units capable of responding, irrespective of the specific pathology causing destruction. CLGR is plastic; supplementation of growth promoters, e.g., retinoic acid or erythropoietin (Epo), further enhances alveolar tissue-capillary formation in remaining lobes but has not further augmented lung function, indicating a structure-function discrepancy in response to exogenous stimulation. This may be because mechanically induced lung growth also increases oxidative stress, which in turn limits growth and remodeling; also newly added tissue-capillaries may distort architecture of the acinus, the fundamental unit of gas exchange, and detract from functional enhancement. Anti-oxidation may be a key factor in resolving the structure-function discrepancy. Oxidative stress, paracrine Epo signaling via its receptor (EpoR), and the circulating anti-oxidative factor αKlotho, are all persistently elevated during post-PNX CLGR. αKlotho acts upstream of EpoR to enhance EpoR cytoprotection in vitro, suggesting that αKlotho may also enhance angiogenic stimulation via the Epo-EpoR axis. We propose that optimal CLGR requires a balance between mechanical signals and cytoprotection, and concurrent αKlotho anti-oxidation may enhance EpoR-stimulated angiogenesis in CLGR. Aim 1 will test the hypothesis that αKlotho and EpoR mutually enhance each other to relieve oxidative stress in the lung, using mice with lung-specific conditional EpoR deletion ± genetic Klotho insufficiency, exposed to oxidant challenge. Aim 2 will test the hypothesis that αKlotho augments EpoR-mediated angiogenic stimulation and acinar remodeling in CLGR to facilitate translation of structural growth into functional gain. We will concurrently deliver nanoparticles containing EpoR and/or αKlotho cDNA to post-PNX young and adult canine lungs, to assess alveolar-capillary regrowth (in vivo CT and electron microscopy), angiogenic factor and progenitor cell distribution, stratified acinar architecture (microCT) and functional compensation. Finally, we will develop and compare (αKlotho+EpoR) cDNA treatment in PNX model with a canine unilateral elastase emphysema model characterized by reduced mechanical stress and elevated inflammatory oxidative stress. These issues of stratified acinar remodeling, growth-stimulation vs. cytoprotection balance, and overcoming structure-function discrepancy in CLGR, have not been examined; they directly impact any intervention aimed at promoting repair and regeneration of the native functioning lung units in destructive lung disease, e.g., emphysema or fibrosis as well as in transplanted or bioengineered lungs.

项目摘要 成年犬右肺切除术（PNX）导致约58%的肺单位损失后， 和微血管机械应力叠加刺激代偿性肺生长和重塑（CLGR） 剩余的肺单位，导致肺泡组织毛细血管再生，恢复约50%的损失 功能这种强大的再生模型模拟了破坏性肺部疾病的后果， 探索适应机制的其余功能肺单位能够作出反应，无论 造成破坏的特定病理学。CLGR是可塑的;补充生长促进剂，例如， 视黄酸或促红细胞生成素（Epo）进一步增强剩余肺叶中的肺泡组织毛细血管形成， 并没有进一步增强肺功能，表明对外源性 刺激.这可能是因为机械诱导的肺生长也会增加氧化应激， Turn限制了生长和重塑;新增加的组织毛细血管也可能扭曲腺泡的结构， 气体交换的基本单位，并减损功能增强。 抗氧化可能是解决结构-功能差异的关键因素。氧化应激，旁分泌 通过其受体（EpoR）和循环抗氧化因子αKlotho的Epo信号传导都是持续的， 在PNX后CLGR期间升高。αKlotho在体外作用于EpoR的上游以增强EpoR的细胞保护， 这表明αKlotho也可能通过Epo-EpoR轴增强血管生成刺激。我们建议 最佳CLGR需要机械信号和细胞保护之间的平衡，同时αKlotho 抗氧化可增强CLGR中EpoR刺激的血管生成。 目的1将检验αKlotho和EpoR相互促进以减轻氧化应激的假设 使用肺特异性条件性EpoR缺失±遗传性Klotho功能不全的小鼠，暴露于 氧化剂挑战目的2将检验αKlotho增强EpoR介导的血管生成的假设。 刺激和腺泡重塑，以促进结构生长转化为功能增益。我们 将同时向PNX后的年轻人和成年人递送含有EpoR和/或αKlotho cDNA的纳米颗粒 犬肺，以评估肺泡毛细血管再生（体内CT和电子显微镜）、血管生成因子和 祖细胞分布、分层腺泡结构（microCT）和功能补偿。最后我们将 在PNX模型中用犬单侧弹性蛋白酶开发和比较（αKlotho+EpoR）cDNA治疗 肺气肿模型，其特征在于降低的机械应激和升高的炎性氧化应激。 这些问题的分层腺泡重塑，生长刺激与细胞保护的平衡，并克服 CLGR结构-功能差异尚未得到检验;它们直接影响任何旨在 促进破坏性肺病中的天然功能肺单位的修复和再生，例如， 肺气肿或纤维化以及移植或生物工程肺。