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.

Public Health Relevance

Lungs can be critically injured in response to lung transplant, high fractions of oxygen, or other insults. Unfortunately our means of determining the severity of these injuries provide non-specific information and are often clearly abnormal only late in the disease process. We will measure serial changes in the capacity of lung tissue to produce energy and correlate these values to a graded capacity of that lung to recover by 7 days after injury. Our studies will develop 2 novel imaging techniques which will for the first time measure injury in the intact rat lung end points which directly relate to the capacity of lung tissue to produce energy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Harabin, Andrea L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Audi, Said H; Clough, Anne V; Haworth, Steven T et al. (2016) 99MTc-Hexamethylpropyleneamine Oxime Imaging for Early Detection of Acute Lung Injury in Rats Exposed to Hyperoxia or Lipopolysaccharide Treatment. Shock 46:420-30
Medhora, Meetha; Haworth, Steven; Liu, Yu et al. (2016) Biomarkers for Radiation Pneumonitis Using Noninvasive Molecular Imaging. J Nucl Med 57:1296-301
Fish, Brian L; Gao, Feng; Narayanan, Jayashree et al. (2016) Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs. Health Phys 111:410-9
Audi, Said H; Jacobs, Elizabeth R; Zhao, Ming et al. (2015) In vivo detection of hyperoxia-induced pulmonary endothelial cell death using (99m)Tc-duramycin. Nucl Med Biol 42:46-52
Medhora, Meetha; Gao, Feng; Glisch, Chad et al. (2015) Whole-thorax irradiation induces hypoxic respiratory failure, pleural effusions and cardiac remodeling. J Radiat Res 56:248-60
Gao, Feng; Fish, Brian L; Szabo, Aniko et al. (2014) Enhanced survival from radiation pneumonitis by combined irradiation to the skin. Int J Radiat Biol 90:753-61
Medhora, Meetha; Gao, Feng; Wu, Qingping et al. (2014) Model development and use of ACE inhibitors for preclinical mitigation of radiation-induced injury to multiple organs. Radiat Res 182:545-55
Nanchal, Rahul; Kumar, Gagan; Majumdar, Tillotama et al. (2014) Utilization of mechanical ventilation for asthma exacerbations: analysis of a national database. Respir Care 59:644-53
Ali, Irshad; Nanchal, Rahul; Husnain, Fouad et al. (2013) Hypoxia preconditioning increases survival and decreases expression of Toll-like receptor 4 in pulmonary artery endothelial cells exposed to lipopolysaccharide. Pulm Circ 3:578-88
Staniszewski, Kevin; Audi, Said H; Sepehr, Reyhaneh et al. (2013) Surface fluorescence studies of tissue mitochondrial redox state in isolated perfused rat lungs. Ann Biomed Eng 41:827-36

Showing the most recent 10 out of 16 publications