Repeated air pollution exposure predisposes to adverse outcomes from acute lung injury

Air pollution exposure is associated with increased risk of developing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). While the possibility of air pollution priming the immune system to exacerbate ALI is postulated, it lacks experimental evidence. NOD-like Receptor X1 (NLRX1) is a mitochondria-localized protein that regulates a variety of cellular functions including inflammation and oxidant generation. Presently, the role of NLRX1 in the context of air pollution-mediated priming of ALI remains unclear. We hypothesized that a subacute ozone (O₃) and ultrafine carbon black (CB) mixed inhalation exposure would prime for worse ALI responses and NLRX1 would exert a protective role. We exposed male C57BL/6J (Nlrx1^+/+) and Nlrx1^-/- mice to a mixture of 250 ppb O₃ and 1 mg/m³ CB 3 hours per day for 5 days a week over 3 weeks by whole body inhalation. After 3 weeks of exposure, we induced ALI by administering 1.5 IU/Kg bleomycin (BLM) and euthanized mice 14 days post-BLM exposure. We assessed survival, lung function, inflammation, lung remodeling and proportions of immune cells.

In Nlrx1^-/- mice air pollution exposure primed for worsened bleomycin-induced survival. The adverse phenotype in Nlrx1^-/- mice was associated with increased inflammation, greater lung function decline and increased collagen deposition. Immune cell phenotyping indicated modulation of macrophages (alveolar and interstitial), neutrophils and CD103⁺ dendritic cells in Nlrx1^-/- exposed and BLM challenged mice.

We identify NLRX1 as a novel mediator for air pollution-induced priming of worsened ALI.