Novel imaging to identify lung mitochondrial injury and predict recovery

识别肺线粒体损伤并预测恢复的新型成像技术

• 批准号: 8708958
• 负责人: ELIZABETH R JACOBS
• 金额: $ 25.77万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708958
• 关键词: Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Albumins; Apoptosis; Bioenergetics; Cell Survival; Clinical; Coenzymes; Data; Dependence; Detection; Deterioration; Diagnosis; Discipline of Nuclear Medicine; Disease; Figs - dietary; Functional disorder; Glutathione; Goals; Histologic; Hyperoxia; Image; Imaging Techniques; Injury; Ischemia; Link; Lung; Lung Capacity; Measurement; Measures; Mediating; Membrane Potentials; Mitochondria; Modality; Modeling; NADH; Necrosis; Optics; Organ; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Oximes; Oxygen; Patients; Pneumonia; Process; Pulmonary Edema; Rattus; Reactive Oxygen Species; Recovery; Reperfusion Injury; Reperfusion Therapy; Risk-Benefit Assessment; Rodent; Role; Safety; Severities; Structure; Structure of parenchyma of lung; Techniques; Testing; Time; Tissues; Transplantation; Vision; X-Ray Computed Tomography; base; cytochrome c; duramycin; imaging modality; improved; in vivo; indexing; injured; lung injury; lung ischemia; minimally invasive; mitochondrial dysfunction; mitochondrial membrane; neutrophil; novel; optical imaging; public health relevance; response; single photon emission computed tomography; technetium Tc 99m 1,2-bis(bis(2-ethoxyethyl)phosphino)ethane; uptake

DESCRIPTION (provided by applicant): Oxygen radical-mediated lung injury may result in settings of lung transplant (ischemia reperfusion; IR), hyperoxia, necrotizing pneumonias and other conditions. The only non-invasive, clinical means (e.g. CT scans or oxygenation) to assess the severity of lung injury are indirect, and they detect damage very late in the process of recovery or deterioration. Common to these injuries is mitochondrial dysfunction, though the causal relationship between mitochondrial dysfunction and injury in lung tissue or the role of mtROS in promoting IR lung injury is not known. The PI's vision is to establish the role of mitochondrial dysfunction in IR injuries and diagnose these injuries using novel minimally invasive techniques based upon deranged mitochondrial function. This information will permit treatment of patients with IR lung injury based upon individualized risk-benefit assessments in real time. We have developed two rodent ischemia reperfusion IR lung injury models: one with substantial but recoverable injury and a second which results in necrotic lung. Our data support altered mitochondrial bioenergetics in these IR injury models and in rodent hyperoxic lung injury. Acute lung injury (ALI) from hyperoxia is particularly attractive as a second model because it is commonly encountered clinically (with Acute Respiratory Distress Syndrome) and it is associated with neutrophilic influx. We introduce two novel in vivo, non-destructive imaging methods for quantifying mitochondrial function that have potential to be transferred very rapidly to the clinical field. We hypothesize that: i) IR stimulates mitochondrial dysfunction and increased mtROS which are mechanistically linked to subsequent apoptosis and decreased lung cell survival as detected biochemically and histologically ii) SPECT/CT and optical imaging can detect altered mitochondrial energetics and apoptosis in vivo. Serial changes in imaging values after IR injury will correlate to the extent of mitochondrial dysfunction and hence organ injury. We will test these hypotheses with four specific aims by addressing 4 important questions. (1) Are mitochondrial dysfunction and mtROS critical determinants of IR lung injury? Do serial changes in mitochondrial bioenergetics correlate with the extent of lung injury? (2) Can we track the severity of rat lung IR injury with single photon emission computed tomography/computed tomography (SPECT/CT) using nuclear medicine agents which target mitochondrial function and apoptosis and are in clinical use for alternative indications. (3) Do mitochondrial redox ratios detected in vivo by optical imaging correlate to sequential changes in mitochondrial function and extent of lung injury? (4) Do SPECT and optical imaging indices of injury correlate to extent of dysfunction in ALI produced by hyperoxia? With our novel means to detect apoptosis and redox injury in vivo, we are poised to examine correlations between altered mitochondrial bioenergetics, severity of changes to lung structure or function and the potential of imaging methods to track these injuries. There is potential to move these modalities quickly to the bedside to improve the outcome for patients with oxidoreductive lung damage related to transplantation, severe pneumonias, hyperoxic exposure or other disorders.

描述（由申请人提供）：氧自由基介导的肺损伤可能导致肺移植（缺血再灌注；IR）、高氧血症、坏死性肺炎和其他病症。评估肺损伤严重程度的唯一非侵入性临床方法（例如 CT 扫描或氧合）是间接的，并且它们在恢复或恶化过程中很晚才检测到损伤。这些损伤的共同点是线粒体功能障碍，但线粒体功能障碍与肺组织损伤之间的因果关系或 mtROS 在促进 IR 肺损伤中的作用尚不清楚。 PI 的愿景是确定线粒体功能障碍在 IR 损伤中的作用，并使用基于线粒体功能紊乱的新型微创技术来诊断这些损伤。这些信息将允许根据个性化的实时风险效益评估对 IR 肺损伤患者进行治疗。我们开发了两种啮齿动物缺血再灌注 IR 肺损伤模型：一种具有严重但可恢复的损伤，另一种导致肺坏死。我们的数据支持这些 IR 损伤模型和啮齿动物高氧肺损伤中线粒体生物能的改变。高氧引起的急性肺损伤（ALI）作为第二种模型特别有吸引力，因为它在临床上很常见（急性呼吸窘迫综合征），并且与中性粒细胞流入有关。我们介绍了两种新颖的体内非破坏性成像方法来量化线粒体功能，这些方法有可能非常快速地转移到临床领域。我们假设：i) IR 刺激线粒体功能障碍并增加 mtROS，这在机制上与随后的细胞凋亡和肺细胞存活率降低有关（如生化和组织学检测）ii) SPECT/CT 和光学成像可以检测体内线粒体能量学和细胞凋亡的改变。 IR损伤后成像值的连续变化将与线粒体功能障碍以及器官损伤的程度相关。我们将通过解决 4 个重要问题来测试这些假设的四个具体目标。 (1) 线粒体功能障碍和 mtROS 是 IR 肺损伤的关键决定因素吗？线粒体生物能学的一系列变化与肺损伤的程度相关吗？ (2) 我们能否使用单光子发射计算机断层扫描/计算机断层扫描 (SPECT/CT) 来追踪大鼠肺 IR 损伤的严重程度，使用核医学药物靶向线粒体功能和细胞凋亡，并在临床上用于替代适应症。 (3) 通过光学成像在体内检测到的线粒体氧化还原比是否与线粒体功能和肺损伤程度的连续变化相关？ (4) SPECT 和光学成像损伤指数与高氧引起的 ALI 功能障碍程度相关吗？通过我们检测体内细胞凋亡和氧化还原损伤的新方法，我们准备检查改变的线粒体生物能学、肺结构或功能变化的严重程度以及追踪这些损伤的成像方法的潜力之间的相关性。有可能将这些方式迅速转移到床边，以改善与移植、严重肺炎、高氧暴露或其他疾病相关的氧化还原性肺损伤患者的预后。