Epigenetic Regulation and Alveolar Macrophage Dysfunction in the Respiratory Immunopathology of Gulf War Illness
Abstract
Respiratory disease is frequently experienced by Veterans affected by Gulf War Illness. Although the biological cause of Gulf War Illness is not yet fully understood, research has shown that chronic inflammation is a primary characteristic of disease. If present in the lung, sustained inflammation can lead to the development of lung cancer, pulmonary obstructive disease, and increased susceptibility to respiratory infections. In Veterans and experimental animal studies, exposure to airborne agents present in the theater of operation, particularly burn pit-associated factors such as fine carbon particles and pesticides, results in inflammation at the lung. Importantly, data from 28 states and the VA Central Cancer Registry shows that the rates of lung cancer among Veterans deployed to the Persian Gulf are significantly greater compared to Veterans who were not deployed. Nevertheless, how such toxin exposures lead to disease and cancer years later has yet to be examined. Macrophages are specialized immune cells that patrol the borders between our bodies and the environment, such as those present in the lung. Macrophages serve as sentinels, constantly sampling the airways for signs of danger. As the first responders of the immune system, macrophages are highly susceptible to inhaled hazards such as smoke, sand/dust, and pesticides present during the Gulf War. In the proposed study, we will examine how exposure to Gulf War-associated toxins can cause sustained lung damage in the mouse. We will then examine if exposure to Gulf War toxins increases the risk of developing lung cancer following exposure to a tobacco carcinogen. These studies will model the increase in lung cancer seen in Veterans who served in the Persian Gulf. We believe that exposure to inhaled toxins affects the macrophages of the lung, causing them to become highly inflammatory. We predict that toxin exposure leads to inflammation by disrupting the method by which inflammatory genes are regulated in these macrophages. Notably, this genetic disruption is maintained in long-lived macrophages and passed on to their daughter cells upon division, resulting in chronic inflammation. We further predict that macrophage inflammation will drive the development and progression of lung cancer when animals are given a tobacco carcinogen. By precisely defining the mechanisms controlling destructive inflammation, we may identify the biological cause of Gulf War-associated respiratory disease. In addition, we believe that if confirmed, the same mechanism may be responsible for the destructive inflammation seen in neurologic disorders, chronic fatigue, and autoimmune disease associated with Gulf War Illness. Finally, these patterns of genetic regulation may be found in cells (macrophages) of the blood, which will serve as a way to predict if Veterans are at increased risk of developing respiratory disease and cancer. To address the need for innovative treatments for Gulf War Illness, we will test the ability of a new class of drugs that affect genetic regulation. These drugs may reduce the inflammation and damage caused by exposure to inhaled toxins. We predict that these drugs will be able to reprogram the toxin-exposed macrophages in the lung, shutting down the genes responsible for destructive inflammation and restoring balanced immunity. We believe that by reducing the inflammation caused by macrophages in the lung, we can inhibit the development of lung cancer. Our studies will examine both male and female animals, providing insight into the role of gender and immunity in disease susceptibility and response to therapy. In addition, these drugs have recently received Food and Drug Administration approval for the treatment of cancers. Re-purposing these compounds for the treatment of Gulf War Illness provides a rapid method to advance effective interventions to immediately help our Veterans. We believe that by blocking inflammation in the lung, we m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910650
Entities
People
- Adam C Soloff
Organizations
- United States Army
- University of Pittsburgh