Prior acute ozone injury dampens Th2 responses to subsequent repetitive ozone exposures in mice

TL;DR

Prior high ozone exposure reduces lung inflammation from later low ozone exposures in mice.

Contribution

The study reveals that prior acute ozone exposure modulates subsequent Th2 immune responses to repeated ozone exposure.

Findings

Mice with prior acute ozone exposure showed reduced immune cell recruitment and inflammation after repeated low-dose ozone.

BALF analysis showed lower levels of Th2-related cytokines like eotaxin and IL-4 in the O3-O3 group.

O3-O3 mice had elevated levels of anti-inflammatory cytokines like IL-10 and IL-12.

Abstract

Ground-level ozone (O3), a criteria air pollutant, can cause significant adverse effects on lung health, including airway inflammation, compromised lung function, and increased susceptibility to lung infections. This study was conceived to determine whether a history of high-concentration O3-induced acute lung injury responsiveness of respiratory tract to low-concentration repetitive O3 exposures. Accordingly, we hypothesized that prior acute O3 exposure would modulate the lung’s Th2 responses to subsequent repetitive O3 exposures. We exposed 8–10-week-old C57BL6/J mice to either filtered air (FA) or 2 ppm O3 for three hours, followed by a three-week recovery period, after which the mice received daily exposures to FA or 1 ppm O3 for four hours over 9 days. We evaluated immune cell recruitment, inflammatory mediators in cell-free bronchoalveolar lavage fluid (BALF) and examined mucous cell metaplasia and epithelial cell injury in lung tissue sections. As expected, FA-FA (no O3 exposure) mice did not exhibit any signs of injury or inflammation. The O3-FA (acute O3 exposure only) groups exhibited baseline immune cell populations and no evidence of MCM suggesting almost complete recovery from acute lung injury. In contrast, FA-O3 group (repetitive O3 exposure only) demonstrated loss of body weight, marked immune cell recruitment, and prominent MCM. These mice also displayed elevated BALF levels of eotaxin, IL-1α, IL-1β, and IL-4, along with increased number of mast cells and FIZZ1+ epithelial cells in the lungs. Compared with FA-O3 group, the O3-O3 group (both acute and repetitive O3) exhibited attenuated responses, as evidenced by diminished eosinophil and lymphocyte counts, and attenuated MCM. BALF analysis revealed lower levels of eotaxin, IL-1α, IL-1β, and IL-4, but elevated levels of G-CSF, KC, IL-6, IL-10, and IL-12 in the O3-O3 group. Furthermore, these mice displayed reduced numbers of mast cells and FIZZ1+ epithelial cells. These findings suggest that prior exposure to acute high-concentration O3 modulates inflammatory and remodeling responses induced by subsequent repeated low-concentration O3 exposures. The findings from this study highlight the health impacts of O3 pollution, particularly in populations experiencing intermittent high-level exposures.

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