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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL116530-02
Application #
8708958
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
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53226