Identifying Novel Immune and Radiographic CT Imaging Signatures of Chronic Bronchiolitis

Principal Investigator: OSTERHOLZER, JOHN J
Institution Receiving Award: MICHIGAN, UNIVERSITY OF
Program: GWIRP
Proposal Number: GW160154
Award Number: W81XWH-17-1-0575
Funding Mechanism: New Investigator Award - New GWI Researcher
Partnering Awards:
Award Amount: $630,000.00


Background: Soldiers returning from deployment to South West Asia during the First Gulf War and Operations Enduring Freedom/Iraqi Freedom/New Dawn commonly report new respiratory symptoms including dyspnea on exertion, cough, and chronic fatigue. Inhalational lung injuries are suspected given the multiple potential exposures to chemical and combustible weapons and environmental toxins (burning oil refineries, combat smoke, burn pits, sulfur mine fires, pesticides, and airborne particulate matter) present in these deployment zones. Our proposal highlights numerous lines of evidence suggesting that these toxins cause chronic bronchiolitis, which is characterized by a chronically abnormal immune response and scarring within small airways (the bronchioles) that results in many of the respiratory symptoms Soldiers experience years after deployment. At present, we still lack a basic understanding of what causes chronic bronchiolitis and how airway injury results in fibrosis. Furthermore, we lack good tests to diagnose chronic bronchiolitis without resorting to a lung biopsy requiring surgery. Lastly, no effective treatments for chronic bronchiolitis have been identified.

Rationale and Objective: Although the cause of deployment-associated bronchiolitis remains uncertain, our proposal provides published and preliminary data suggesting that injury to a highly specific subset of cells, called club cells, within the airway epithelium is crucially important to the development of chronic bronchiolitis. Numerous toxins capable of causing club cell injury are present in deployment zones, and we specifically show that the pattern of chronic bronchiolitis in the lungs of Soldiers with chronic bronchiolitis (viewed using a microscope) is similar to the pattern of injury identified in mice, which were genetically manipulated to make them uniquely susceptible to repetitive club cell injury. Our studies suggest that a subset of immune cells called monocytes and macrophages may be important contributors to chronic bronchiolitis. We have also developed a new radiographic imaging analysis program, called parametric response mapping, which we believe can help diagnose chronic bronchiolitis. In this proposal, we specifically hypothesize that lung monocytes and macrophages contribute to a unique and abnormal immune and radiographic pattern of chronic bronchiolitis resulting from club cell injury. Collectively, the objective of this proposal is to better understand chronic bronchiolitis and to identify novel immune and radiographic markers of this disease that may help diagnosis and treat this condition.

Research Plan: Aim 1 will utilize two models of airway injury in mice to identify unique immune signatures of chronic bronchiolitis in the lungs, lung fluid, and peripheral blood. Aim 2 will test whether impairing the arrival of monocytes and macrophages to airway-injured lungs will prevent chronic bronchiolitis in mice. Aim 3 will test whether a parametric response mapping performed on CT (computed tomography) scans obtained from mice and Soldiers with chronic bronchiolitis can identify a unique radiographic signature, called functional small airways disease, that may help us better diagnose chronic bronchiolitis and follow its progression over time or response to treatment.

Applications and Impact: Our proposed studies apply to the respiratory health of Gulf War Veterans who may have developed chronic bronchiolitis given their potential exposure to numerous respiratory toxins during deployment. Chronic bronchiolitis can cause cough, shortness of breath, and fatigue and thus contribute to the constellation of symptoms experienced by Soldiers diagnosed with Gulf War Illness. Our results will also apply to Soldiers deployed to Southwest Asia since the first Gulf War and to those who may be deployed to this region in the future. This study may yield better tests to diagnose chronic bronchiolitis in the next 3 to 5 years in a manner that no longer relies on an invasive lung biopsy requiring surgery. Development of this model may yield new treatments for this condition in 5 to 10 years. This study utilizes animal models of chronic bronchiolitis and CT scans already obtained for clinical purposes; thus, it does not entail any risk to a Soldier’s health. Relationships between airway inflammation and fibrosis play a prominent role in other health conditions affecting Soldiers and Veterans including asthma and chronic obstructive lung disease (also known as COPD), thereby increasing the importance of this proposal. The impact of these studies is further enhanced by the addition of the Principal Investigator, an experienced lung research scientist, as a new investigator to field of Gulf War Illness.