Airborne pollution is well documented as a risk factor for multiple airway diseases, and is implicated in aggravating autoimmunity, both systemically and in the lung. The mechanisms and true importance in human disease remains very unclear. In this grant we investigate the importance of particulate matter (PM), and specifically polycyclic aromatic hydrocarbons (PAHs) in PM, to enhance Th17 differentiation and inflammation in the lung, which aggravates environmentally induced airway disease (EIAD). Our interest in this topic stems from experience with lung transplantation, where half of recipients develop bronchiolitis obliterans syndrome (BOS) within 5 years of transplantation, leading to re-transplantation or death. BOS, considered to be chronic rejection of lung allografts, is thought to be the consequence of increased Th17 differentiation in the lung leading to graft destruction, but the mechanism is unknown and increased immunosuppression has not been successful in its treatment. In support of an environmental role in BOS are the recent reports showing that lung transplant recipients exposed to higher levels of atmospheric PM are at greater risk for development of BOS. Our overarching hypothesis is that EIADs including BOS are the consequence of the lung's intimate relationship with the airborne environment. We predict that subtle differences in the chemical constituencies of airborne PM have significant consequences for the normal immunology of this organ. The recent finding that the AHR plays a central role in the regulatory T cell (Treg)/Th17 balance, where some ligands of the AHR enhance Treg differentiation and others enhance Th17 differentiation has led us to predict that PAHs in PM are responsible for toxicant-induced inflammation seen after exposure to PM. We will explore the following aims: Aim 1: Identify the components contained in PM that impact T-cell differentiation. Aim 2: Define the AHR signal transduction steps required for the enhancement of IL-17 and IL-22 generation by PM. Aim 3: Determine whether PM exposure augments a pathogenic T cell response in a murine airway inflammation model and utilize novel transgenic mice to identify requirements of AHR expression. The unique features of this grant are the novelty of considering BOS as an EIAD, the ability we have based on our expertise to examine specific components of PM and their interaction with the AHR, the numerous recombinant mouse models at our disposal, and our ability to compare standard reference materials to real- world samples to develop and test a signature for components of PM that enhance airway inflammation. The connections of this project to public health are supported by the high incidence of EIAD, including asthma, emphysema, chronic bronchitis, and interstitial fibrosis, in addition to BOS. We predict that our findings will allow both avoidance strategies that will arise from our ability to predict which exposures are most likely to aggravate airway disease, to novel targets for treatment of EIAD. This will save the health care system billions of dollars in additio to minimizing significant morbidity and mortality of these common diseases.
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NIH ExPorter