ABSTRACT
This application is in response to the NOSI of Promoting Fundamental and Applied Research in Inflammation
Resolution, in particular to NIEHS’ interest in inflammation resolution related to environmental exposure. It is
increasingly recognized that the immune response to an inflammatory stimulus involves specialized pro-
resolving mediators (SPMs) that orchestrate the lung’s return to homeostasis by resolving cellular and tissue
inflammation. However, little data in humans are available concerning the effects of PM2.5, a ubiquitous air
pollutant, on SPMs and inflammation resolution. This is in marked contrast to the large body of literature on the
proinflammatory response to PM2.5. Here we hypothesize that PM2.5 impairs cellular biosynthesis and kinetics of
SPMs, leading to compromised resolution of inflammation in the airway. As airway inflammation is a hallmark of
asthma, it is highly plausible but yet to be confirmed that individuals with asthma are less capable of resolving
pollution-induced inflammation. No data are available to support a sex-specific hypothesis on inflammation
resolution, despite the known sex-difference in proinflammatory responses to air pollution. Hence, we further
hypothesize the effects of PM2.5 on inflammation resolution differ between people with and without asthma and
between men and women. We propose to test these hypotheses in a translational study framework by
leveraging an existing panel study of air pollution health effects. Our approach comprises of ex vivo cell culture
experiments focusing on molecular mechanisms of SPM biosynthesis and resolution kinetics (Aim 1) and a panel
study aiming to examine SPM-PM2.5 relationships in vivo (Aim 2) and to examine potential SPMs mediation of
the PM2.5 effects on clinical outcomes (Aim 3). To maximize the translatability of the mechanistic findings in Aim
1, we will use primary airway epithelial cells collected from among the panel study participants and will use
composition-characterized PM2.5 collected in London, UK, where participants reside. In Aim 2 panel study, 40
participants with and 40 without asthma will be measured 4 times longitudinally for SPMs in nasal fluid and
induced sputum, representing the first portal of PM2.5 entry and the lung, respectively. Detailed personal PM2.5
doses and internal doses (biomarkers) of source-specific PM2.5 constituents hours to days prior to SPM
measurements will be associated with sputum and nasal SPM concentrations. We anticipate to see differences
by asthma and sex, respectively, in the time-concentration profile. In Aim 3, by leveraging the panel study’s rich
dataset on health outcomes of clinical relevance, we will examine the mediating effects of SPMs on the exposure-
outcome associations at the key time-points of inflammatory and resolution responses identified in Aims 1 and
2. Taking all together, we anticipate to link molecular mechanisms regulating SPM biosynthesis with resolution
kinetics and clinically-relevant functional and inflammatory responses to PM2.5. The study will generate real-life
data to better understand the role of SPM in resolving pollution-induced inflammation in the airways of asthmatics
versus non-asthmatics and those of men versus women.
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