Pathophysiologic impacts of tire and road wear particles in healthy and inflamed lungs

The National Institute of Environmental Health Sciences awarded West Virginia University Research Corporation $406,930 on September 4, 2026, under the Environmental Health program (CFDA 93.113) to conduct pathophysiological research on tire and road wear particles in healthy and inflamed lungs.

The project addresses a three-part knowledge gap: how environmental conditions including temperature and ozone levels interactively impact the formation of 6PPD-Q on tire and road wear particles; whether inhalation exposure to 6PPD and 6PPD-Q poses pulmonary and systemic hazard; and how wear particles interact with pre-existing lung inflammation or disease. The research team will perform in vitro and in vivo studies to examine the role of NLRX1, a mitochondria-localized pattern recognition receptor, in tire and road wear particle-induced inflammatory and metabolic responses. Preliminary data demonstrate ozone-mediated changes in 6PPD-Q levels, NLRX1-dependent lung inflammation, and aggravation of pre-existing inflammation by exposure to wear particles.

Work is performed in Morgantown, West Virginia, with a period of performance through June 30, 2031. This project grant funds mechanistic environmental health research aligned with NIEHS's mission to investigate how environmental exposures affect biological systems and translate that knowledge to reduce disease and promote health.

Abstract

Road and tire wear particles (trwp) are non-exhaust emission particles of significant concern due to their rapidly increasing levels and transformations in the environment that release toxic chemicals. Tire-derived particles account for up to 26% of microplastics in the environment. While exhaust emissions are the focus of current regulatory oversight, unfortunately, non-exhaust emissions are not regulated. Additionally, while the toxicity of trwp has recently garnered significant attention, the mechanistic basis of its toxic effects and the role of these particles in modulating pre-existing inflammation have yet to be elucidated. We identify a three- fold knowledge GAP: 1) how do environmental conditions (temperature and O3 levels) interactively impact 6PPD-q formation on trwp, 2) does inhalation exposure to 6PPD and 6PPD-q from trwp pose a pulmonary and systemic hazard, and 3) how do wear particles interact with pre-existing inflammation/lung disease. We are a team of experts in inhalation toxicology, particle chemistry, immune/inflammatory responses, redox responses, and mitochondrial biology that will perform in vitro and in vivo studies to answer these questions. Nucleotide-binding oligomerization domain, leucine-rich repeat containing X1 (NLRX1) is a mitochondria-localized pattern recognition receptor implicated in inflammation and metabolic pathways. However, its contribution in air pollution and trwp-induced biological responses is not described. Our preliminary data demonstrates O3-mediated changes in 6PPD-q levels, NLRX1-dependent lung inflammation and significant aggravation of pre-existing inflammation by trwp exposure. Based on available literature and preliminary data, we hypothesize that O3 and heat interactively transform trwp into chemically, biologically and oxidatively reactive particles that induce an inflammatory response and aggravate pre-existing inflammation through NLRX1-mediated pathways. In aim 1, we will determine optimal environmental conditions leading to the transformation of trwp from the road simulator and quantify oxidants, surface functional group changes and 6PPD/6PPD-q. Additionally, we will determine the inhalation hazard of 6PPD-q adsorbed on ultrafine particles. In aim 2, we will investigate the mechanisms of in vitro toxicity of trwp using primary macrophages and epithelial cells, as well as relevant cell lines and will apply genetic and therapeutic manipulation of NLRX1 to elucidate its contribution. In aim 3, we will determine trwp-induced inflammation and pulmonary function decline in NLRX1+/+ and NLRX1-/- mice. We will define the impact of trwp exposure on lipopolysaccharide-induced innate inflammation and house dust mite extract-induced allergic inflammation/lung function decline. Finally, the inflammation-reducing benefit of an NLRX1 agonist (NX-13) will be tested. This proposal will provide an understanding of how environmental conditions dictate trwp transformations leading to adverse biological outcomes by providing novel mechanistic insights into cellular and organ dysfunction during both normal and pre-existing inflammatory conditions.