Novel Diagnostics to Detect Lung Injury

检测肺损伤的新型诊断方法

• 批准号: 8543980
• 负责人: ELIZABETH R JACOBS
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543980
• 关键词: Adenine; Adopted; Affect; Amobarbital; Apoptosis; Biochemical; Bioenergetics; Brain; Bronchiolitis Obliterans; Caring; Cell Death; Cell Survival; Cells; Cessation of life; Chest; Chronic Obstructive Airway Disease; Clinical; Coenzymes; Complex; Crush Injury; Cyclosporine; Cystic Fibrosis; Data; Decision Making; Detection; Dinucleoside Phosphates; Discipline of Nuclear Medicine; Electrons; FADH2; FDA approved; Figs - dietary; Fluorescence; Functional disorder; Generations; Glutathione; Hand; Heart; Histologic; Human; Image; Imaging Techniques; Immunosuppressive Agents; In Situ Nick-End Labeling; Injury; Intervention; Ischemia; Label; Learning; Left lung; Life; Lung; Lung Transplantation; Lung diseases; Measures; Mediating; Metabolic; Methods; Methylprednisolone; Mitochondria; Modeling; Monitor; Morbidity - disease rate; NADH; Necrosis; Nicotinamide adenine dinucleotide; Optics; Organ; Oxidation-Reduction; Oxidative Phosphorylation; Oximes; Pathology; Pharmaceutical Preparations; Pneumonia; Positioning Attribute; Process; Protocols documentation; Pulmonary Fibrosis; Pulmonary Hypertension; Rattus; Reactive Oxygen Species; Recovery; Reperfusion Injury; Reperfusion Therapy; Respiratory physiology; Risk Factors; Rodent; Role; Safety; Signal Transduction; Staging; Staining method; Stains; Steroids; Structure; Technetium 99m; Technetium Tc 99m Exametazime; Techniques; Testing; Time; Tissues; Translating; Transplantation; Transplanted Lung Complication; Vascular blood supply; Veterans; X-Ray Computed Tomography; caspase-3; clinical application; duramycin; fluorescence imaging; graft failure; imaging modality; imaging probe; improved; in vivo; indexing; inhibitor/antagonist; lung injury; lung ischemia; mitochondrial dysfunction; mitochondrial permeability transition pore; novel; novel diagnostics; novel therapeutic intervention; operation; optical imaging; prevent; prognostic; public health relevance; sedative; single photon emission computed tomography; tool

DESCRIPTION (provided by applicant): Experts in lung transplantation agree that ischemia is a recognized risk factor for all postlung transplant problems. Better non-invasive methods to detect ischemia post transplant would provide a window to modify therapy, and thereby reduce morbidity of veterans from these complications. Ischemia-reperfusion (IR) lung damage is also encountered clinically in conditions beyond lung transplantation, including necrotizing pneumonias, or crush injury to the chest (e.g Farivar et al, 2005), all injuries that frequently affect veterans. Substantial evidence supports the role of mitochondrial dysfunction and mitochondrially derived reactive oxygen species (mtROS) in IR injuries to the brain and heart (Stowe & Camara, 2009). Our preliminary data support a critical role for mitochondria in a rat model unilateral lung IR injury, a model of lung transplant which eliminates immunological or drug induced pathology in order to focus exclusively on IR injury. We introduce 2 absolutely novel non-destructive methods to track apoptosis and the redox state in intact IR lung, methods that can be rapidly translated into the clinical field. The first is single photon emission computed tomography/computed tomography (SPECT/CT) imaging, using 99m Tc-duramycin (DU) and 99m Tc- hexamethylpropyleneamine oxime (HMPAO) to detect cell death/apoptosis and gluthathione/redox status respectively. The second is fluorescence optical imaging to follow the redox ratio (RR) of lung. We hypothesize that: (i) IR stimulates mitochondrial complex I dysfunction which leads to subsequent apoptosis and decreased cell survival as detected biochemically and histologically (ii) SPECT/CT and optical imaging can detect and quantify apoptosis or altered mitochondrial bioenergetics in vivo. Changes in the values of these imaging endpoints after IR will correlate with histological injury and some indices of mitochondrial dysfunction (iii) treatment with agents that prevent opening of mitochondrial permeability transition pore (mPTP) and those that are used clinically to prevent rejection will protect against lung injury as detected by SPECT/CT or optical imaging, and this protection will correlate to improved indices of mitochondrial function. We will test these hypotheses with three specific objectives/aims. (1) To use SPECT and nuclear medicine probes which target apoptosis/necrosis or oxidoreductive state to detect unilateral IR lung injury in vivo We will correlate serial SPECT data after IR injury to histological and biochemical evidence of apoptosis/necrosis one week after ischemia. (2) To employ optical imaging which detects the oxidoreductive state of tissue to follow IR lung injury in vivo. The mitochondrial metabolic coenzymes Nicotinamide Adenine Dinucleotide (reduced form is NADH) and Flavine Adenine Dinucleotide (FAD) are the primary electron carriers in oxidative phosphorylation. NADH and FAD (oxidized form of FADH2) are autofluorescent and can be monitored by optical techniques without the need for exogenous labels. (3) To investigate the potential of our novel imaging methods to detect protection from IR injury by agents which act on complex I and the mitochondrial permeability transition pore (mPTP) and that are used clinically in lung transplantation. With our novel means to detect apoptosis and redox injury and a survival model of lung IR injury, we are poised to examine the potential of these non-destructive methods to track ischemic Injury. Though not used routinely for detection of lung injury, SPECT imaging with HMPAO is already in clinical use with well established safety profiles. With translational evidence of prognostic value, these imaging modalities can be adapted readily to improve the care of veterans with IR lung damage. We are uniquely positioned to test novel therapeutic interventions to improve IR lung injury with prognostic and mechanistic information in hand.

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