TRP Channels and Air Pollution

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Project Summary/Abstract: Breathing unhealthy amounts of particulate matter (PM) in polluted air is unavoidable for many people. Currently, our knowledge of specific biochemical interactions that link exposure to the many adverse health effects of PM is incomplete, as is our ability to directly treat and/or prevent these effects. In this study we will build upon our work establishing a novel mechanistic paradigm for how PM can cause deleterious effects in the lungs, involving activation of the transient receptor potential ankyrin-1 (TRPA1), melastatin-8 (TRPM8) and vanilloid-1 (TRPV1) ion channels. Our work shows that different types of PM activate different TRP channels, often leading to specific effects that are relevant to human respiratory disease causation and acute exacerbation. Thus, a continued in- depth assessment of this mechanistic paradigm has the potential to provide crucial knowledge for understanding the basis for respiratory malaise associated with PM, and to further our understanding of the precise contributions of TRP channels to environmentally-sensitive lung diseases such as asthma. Additionally, by establishing fundamental mechanisms that regulate pathophysiological outcomes associated with TRP channel activation by PM, our research could reveal innovative strategies for developing interventions to possibly treat and/or prevent environmental lung diseases. The current studies are motivated by results showing that differential activation of TRPA1, M8, and V1 in human lung cells by PM is coupled to pro-inflammatory and other responses that affect human respiratory disease- related pathways and phenotypes, generally referred to herein as “PM toxicity.” Further, there are species- specific differences in TRP channel responses to PM, suggesting that rodents may not adequately model TRP- dependent mechanisms of PM toxicity in humans. We opine this could be an important barrier for translating mechanistic findings from rodent models to humans, and for developing effective interventions. Finally, we have found that TRPA1, M8, and V1 single-nucleotide polymorphisms (SNPs) can modulate cellular responses to certain forms of PM, as well as ostensibly cause poorer asthma symptom control in children. Also, the TRPV1 I585I/V SNP genotype correlates with the diagnosis and severity of asthma and chronic rhinosinusitis (CRS). Thus, assessment of mechanisms by which selected TRP SNPs affect cellular responses to PM, as well as asthma control, could reveal prognostic biomarkers of hypersensitivity to PM, and criteria for personalizing medical care. Our hypothesis is: Activation of TRPA1, M8 and/or V1 by PM represents a pivotal event underlying the toxic effects of PM. The specific aims are to: 1) Determine mechanisms and the significance of species- specific TRP channel activation by PM; 2) Elucidate the basis and toxicological significance of TRPV1 I585I/V- dependent TRPA1 expression by human lung epithelial cells; and 3) Quantify the impact of TRPA1, M8, and V1 genetics in environmental exacerbation of asthma.