Dynamic Interaction of Airborne Biohazards in Rheumatoid Arthritis-Associated Lung Disease
Abstract
Background: FY20 PRMRP Topic Areas: Rheumatoid Arthritis (RA) and Respiratory Health. This unique research project is to investigate the combination of both airborne hazard-induced respiratory health disease and RA. This will be accomplished utilizing a novel co-exposure mouse model with complementary human studies. It is proposed that airborne hazards encountered by military personnel, first responders and some Veterans Affairs patients are driving RA risk and RA-lung disease. The partnering PIs and multidisciplinary team (experts in lung disease and arthritis, joined by Department of Defense personnel) will address these PRMRP topic areas: 1) Conduct research to better understand the relationship between host factors and airborne pollution hazards in developing RA and RA-lung disease through exploiting a newly established co-exposure animal model. 2) Conduct research to better characterize and understand the preclinical (early) disease stage of RA/RA-lung disease for early diagnosis, treatment, and biomarker identification. Respiratory-related deaths are the most over-represented cause of death in men and women with RA, and respiratory disease manifestations are far more common in men than women with RA. Among U.S. military Veterans, arthritis is a leading cause of disability and the second leading cause of medical discharge from the U.S. Army. One in three Veterans is diagnosed with arthritis, compared to one in four members of the general U.S. population. In general, various airborne biohazard exposures are implicated as disease risk factors for both RA and RA-associated lung disease and include not only cigarette smoke but also exposures related to pollution, farming, construction, and mining among others. Other exposures potentially related to military duties (burn pits, organic dust, military waste disposal) and first responder exposures (flooded buildings, high air pollution environments, organic dust) have also been implicated. These exposures are strongly linked to lung disease (e.g., asthma, interstitial lung disease, emphysema) as well as inflammatory lung disease complicating RA. Emerging human observations suggest that the autoimmune reactions that characterize RA may be initiated in lung tissues exposed to biohazards. In mice, repeated inhalant exposures to organic dust extracts (i.e., dust from hog confinement facilities) induced protein modifications in the lungs that are targeted by RA-specific autoantibodies. Intriguingly, the link between these airborne environmental and occupational exposures and RA risk is particularly strong in men and less clear in women. Correspondingly, it has been demonstrated that male mice co-exposed to inhalant organic dust extract and arthritis induction are more susceptible to lung fibrosis and severe arthritis compared to female mice. The mechanism explaining this sex difference is not known. Therapeutic options for RA-associated lung disease are also quite limited. As such, there are no treatment guidelines to assist clinicians in management. Moreover, there are no known diagnostic tests predictive of the development or progression of RA-associated lung. Anti-citrullinated protein antibodies or ACPA are a cardinal feature of RA, but are not predictive of incident lung disease. Thus, there is an urgent and unmet need to identify predictive blood tests and alternative management approaches to reduce disease burden and mortality for this patient population. Rationale: This innovative conceptual research design will advance the understanding how airborne pollution hazards interplay with systemic autoimmunity/arthritis to potentiate disease and to define sex differences and relevant cellular and protein biomarkers and targets. The prototype airborne biohazard will be the microbial component lipopolysaccharide (LPS; endotoxin, cell wall component of gram-negative bacteria) as it is a main biologic component in several relevant high air pollution settings for the animal
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110929
Entities
People
- Ted R Mikuls
Organizations
- United States Army
- University of Nebraska Medical Center