Hyperpolarized Xenon-129 MRI: a new multi-dimensional biomarker to determine pulmonary physiologic responses to COPD therapeutics

超极化 Xenon-129 MRI：一种新的多维生物标志物，用于确定慢性阻塞性肺病治疗的肺部生理反应

• 批准号: 10084708
• 负责人: Kun Qing
• 金额: $ 78.66万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084708
• 关键词: 3-Dimensional; Address; Adrenal Cortex Hormones; Affect; Aging; Agonist; Air Movements; Alveolar; Anatomy; Anti-Inflammatory Agents; Antiinflammatory Effect; Biological Markers; Blood; Bronchodilation; Bronchodilator Agents; Cause of Death; Characteristics; Chemicals; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clinical assessments; Complex; Complex Mixtures; Correlation Studies; Data; Development; Diagnosis; Diagnostic; Diagnostic Sensitivity; Disease; Disease Progression; Dropout; Erythrocytes; Exhibits; FDA approved; Fostering; Functional Imaging; Functional disorder; Future; Gases; High Resolution Computed Tomography; Human; Image; Imaging Techniques; Inflammation; Inhalation; Intervention; Life; Location; Lung; Magnetic Resonance Imaging; Maps; Measurement; Measures; Microscopic; Monitor; Muscarinic Antagonists; Outcome; Outcome Study; Pathogenesis; Pathologic; Patients; Penetrance; Pharmacology; Phase; Phenotype; Physiological; Physiology; Protocols documentation; Protons; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Quality of life; Research; Research Design; Resistance; Resolution; Respiratory physiology; Sensitivity and Specificity; Severities; Severity of illness; Smoker; Staging; Structure of parenchyma of lung; Surrogate Endpoint; Symptoms; Therapeutic; Tissues; United States; Xenon; airway obstruction; base; chest computed tomography; cigarette smoke; clinically relevant; cohort; disease phenotype; experience; fluticasone; high resolution imaging; imaging study; improved; in vivo; interest; lung volume; multimodality; non-invasive imaging; novel; novel marker; post intervention; potential biomarker; pulmonary function; recruit; response; specific biomarkers; therapy design; tool; treatment response; uptake; ventilation

Chronic Obstructive Pulmonary Disease (COPD) is diagnosed by pulmonary function test (PFT). PFT is commonly used to evaluate the severity and therapeutic response in COPD. However, complex mixture of COPD phenotypes requires a diagnostic tool with abilities to evaluate broader aspects of lung pathophysiology, and this is the primary reason why PFTs do not provide sufficient correlation with disease status and progression to serve as a reliable surrogate endpoint. What is needed is a quantitative and comprehensive set of COPD biomarkers that can provide phenotyping and staging of COPD, rapid assessment of response to a broad range of therapies, and tracking the progression of disease. The hope is that the hyperpolarized xenon magnetic resonance imaging (HXe MRI) could diagnose and intervene patients at the earliest stages of COPD, guide the selection of appropriate therapies, and extend life. In this proposal, two HXe MRI assessments will be performed. (1) A single sequence that combines a high-resolution image of inhaled HXe with a proton image acquired in the same breath-hold will provide the fraction of the lung volume with compromised airflow. (2) A new imaging protocol that exploits xenon's chemical shift sensitivity to the separate tissue compartments of the lung allows a detailed mapping of gas exchange through lung tissue and into the red blood cells. We hypothesize that these HXe MRI signatures will access physiologic information that were previously inaccessible by the conventional PFT and multimodality CT of chest, (MDCT). We also hypothesize that these imaging signatures will enhance our ability to evaluate COPD phenotypes and disease status better than the PFT and MDCT. Higher HXe MRI resolution based on the anatomy of the lung will further enhance the diagnostic sensitivity and specificity. In aim 1, we will perform a study of the correlation of imaging signatures of COPD with conventional assessments (PFT, MDCT and clinical outcomes). In aim 2, we will evaluate changes in the lung physiology of the patients with well-characterized COPD after being serially treated with three standard COPD therapies, long acting muscarinic antagonist (umeclidinium) and long acting beta-agonist (vilanterol) to improve ventilation, and inhaled corticosteroid (fluticasone) to potentially affect the inflammation in tissues. Our study design offers both cross-sectional and longitudinal information. Eighty treatment-naïve subjects will be evaluated at baseline, after two serial 30-day courses of umeclidinium/vilanterol and fluticasone. The 320 assessments, considered independently, will determine correlations between functional imaging signatures and conventional metrics which include PFT, MDCT, and clinical outcomes. Within-subject temporal alterations of the HXe MRI imaging will be evaluated as potential biomarkers to assess COPD phenotypes and disease status, both of which we anticipate to deepen our basic mechanisms contributing to the genesis of COPD and to promote development of new strategies to diagnose and treat COPD.

慢性阻塞性肺疾病 (COPD) 通过肺功能测试 (PFT) 进行诊断。 通常用于评估慢性阻塞性肺病的严重程度和治疗反应，但是，这些因素是复杂的。 COPD 表型需要能够评估更广泛的肺病理生理学方面的诊断工具， 这就是 PFT 无法与疾病状态和疾病提供足够相关性的主要原因 作为可靠的替代终点，需要的是一套定量且全面的进展。 COPD 生物标志物可以提供 COPD 表型和分期，快速评估对慢性阻塞性肺疾病的反应 广泛的治疗方法，并跟踪疾病的进展，希望是超极化氙。 磁共振成像（HXe MRI）可以在慢性阻塞性肺病的早期阶段诊断和干预患者， 指导选择适当的疗法并延长生命 在该提案中，将进行两项 HXe MRI 评估。 (1) 将吸入的 HXe 的高分辨率图像与质子相结合的单个序列 在相同的屏气中获取的图像将提供气流受损的肺体积的分数。 (2) 一种新的成像方案，利用氙对单独组织区室的化学位移敏感性 肺部的图像可以详细绘制通过肺组织并进入红细胞的气体交换。 追求这些 HXe MRI 特征将访问以前的生理信息 传统 PFT 和胸部多模态 CT (MDCT) 无法实现这些。 影像特征将增强我们评估 COPD 表型和疾病状态的能力 基于肺部解剖结构的更高 HXe MRI 分辨率将进一步增强 PFT 和 MDCT。 在目标 1 中，我们将研究影像特征的相关性。 通过常规评估（PFT、MDCT 和临床结果）对 COPD 进行评估 在目标 2 中，我们将评估。 具有明确特征的慢性阻塞性肺病患者在接受连续治疗后肺部生理学的变化 三种标准的慢性阻塞性肺病疗法，长效毒蕈碱拮抗剂（umeclidinium）和长效β-激动剂 （维兰特罗）改善通气，吸入皮质类固醇（氟替卡松）可能会影响炎症 我们的研究设计提供了 80 个未经治疗的横向和纵向信息。 受试者将在两次连续 30 天的 umeclidinium/vilanterol 疗程后进行基线评估 320 项独立评估将确定功能之间的相关性。 影像特征和传统指标，包括 PFT、MDCT 和临床结果。 HXe MRI 成像的时间变化将被评估为评估 COPD 的潜在生物标志物 表型和疾病状态，我们预计这两者都会加深我们的基本机制，有助于 慢性阻塞性肺病的起源并促进开发诊断和治疗慢性阻塞性肺病的新策略。

项目成果

Clinical Impact of Multidisciplinary Outpatient Care on Outcomes of Patients with COPD.

多学科门诊护理对慢性阻塞性肺病患者预后的临床影响。

• DOI: 10.2147/copd.s225156
• 发表时间: 2020
• 期刊: International journal of chronic obstructive pulmonary disease
• 影响因子: 2.8
• 作者: Mansoor,Sahar;Obaida,Zaid;Ballowe,Lorna;Campbell,AmandaR;Patrie,JamesT;Byrum,TimothyD;Shim,YunM
• 通讯作者: Shim,YunM

Evaluation of Regional Lung Function in Pulmonary Fibrosis with Xenon-129 MRI.

• DOI: 10.3390/tomography7030039
• 发表时间: 2021-09-15
• 期刊: Tomography (Ann Arbor, Mich.)
• 作者: Mata J;Guan S;Qing K;Tustison N;Shim Y;Mugler JP 3rd;Altes T;Huaromo J;Mehrad B
• 通讯作者: Mehrad B

Number, activation, and differentiation of circulating fibrocytes correlate with asthma severity.

• DOI: 10.1016/j.jaci.2015.07.037
• 发表时间: 2016-03
• 期刊: The Journal of allergy and clinical immunology
• 作者: Shipe R;Burdick MD;Strieter BA;Liu L;Shim YM;Sung SS;Teague WG;Mehrad B;Strieter RM;Rose CE Jr
• 通讯作者: Rose CE Jr

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice.

• DOI: 10.1038/s41467-021-25590-8
• 发表时间: 2021-09-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bisht K;Okojie KA;Sharma K;Lentferink DH;Sun YY;Chen HR;Uweru JO;Amancherla S;Calcuttawala Z;Campos-Salazar AB;Corliss B;Jabbour L;Benderoth J;Friestad B;Mills WA 3rd;Isakson BE;Tremblay MÈ;Kuan CY;Eyo UB
• 通讯作者: Eyo UB

Measures of ventilation heterogeneity mapped with hyperpolarized helium-3 MRI demonstrate a T2-high phenotype in asthma.

• DOI: 10.1002/ppul.25303
• 发表时间: 2021-06
• 期刊: Pediatric pulmonology
• 影响因子: 3.1
• 作者: Gerald Teague W;Mata J;Qing K;Tustison NJ;Mugler JP;Meyer CH;de Lange EE;Shim YM;Wavell K;Altes TA
• 通讯作者: Altes TA