A high docosahexaenoic acid diet alters lung inflammation and recovery following repetitive exposure to aqueous organic dust extracts

Abstract

Agricultural workers, especially those who work in swine confinement facilities, are at increased risk for developing pulmonary diseases including asthma, chronic obstructive pulmonary disease, and chronic bronchitis due to exposures to fumes, vapors, and organic dust. Repetitive exposure to agricultural dust leads to unresolved inflammation, a common underlying mechanism that worsens lung disease. Besides occupational exposure to dusts, diet also significantly contributes to inflammation and disease progression. Since DHA (docosahexaenoic acid), a polyunsaturated omega-3 fatty acid and its bioactive metabolites have key roles in inflammation resolution, we rationalized that individuals chronically exposed to organic dusts can benefit from dietary modifications. Here, we evaluated the role of DHA in modifying airway inflammation in a murine model of repetitive exposure to an aqueous extract of agricultural dust (three-week exposure to swine confinement dust extract, HDE) and after a one-week resolution/recovery period. We found that mice fed a high DHA diet had significantly increased bronchoalveolar lavage fluid (BALF) levels of DHA-derived resolvins and lower TNF α along with altered plasma levels of endocannabinoids and related lipid mediators. Following the one-week recovery we identified significantly reduced BALF cellularity and cytokine/chemokine release along with increased BALF amphiregulin and resolvins in DHA diet-fed versus control diet-fed mice challenged with HDE. We further report observations on the effects of repetitive HDE exposure on lung Ym1+ and Arg-1+ macrophages. Overall, our findings support a protective role for DHA and identify DHA-derived resolvins and endocannabinoids among the potential mediators of DHA in altering airway inflammation in chronic agricultural dust exposure.

Sex-Specific Differences in Resolution of Airway Inflammation in Fat-1 Transgenic Mice Following Repetitive Agricultural Dust Exposure

“…Since the most significant changes we observed in our model was in the male sex (as in Fat-1 mice with TPPU), we focused our gene expression studies to male sex. NanoString gene expression analysis identified differentially regulated pathways consistent with our previous results ( Dominguez et al, 2020 ; Ulu et al, 2021b ) indicating that immune cell activation, cell proliferation, wound healing and transport pathways were altered following 3-weeks DE exposure. In an In-depth analysis both using STRING database protein-protein interaction and NanoString advanced analyses, we also identified changes in NFκBIA, response to macrophage colony stimulating factor, immune clearance, and neutrophil aggregation between the two genotypes ( Figure 4 ).…”

“…We observed similarly significant results for the infiltrating neutrophils but not for macrophages ( Figures 1B,C ). This increase in neutrophil numbers is consistent with the cellular signature of repetitive DE exposure ( Nordgren et al, 2014 ; Nordgren et al, 2013 ; Ulu et al, 2021b ; Warren et al, 2017 ). With regards to eosinophils, we did not detect any differences among the groups ( Figure 1D ).…”

“…Lung histopathology was evaluated in H&E-stained paraffin-embedded tissue sections mounted on slides to evaluate dust-induced lung inflammation ( Figure 3 ). We have previously shown that total number of lymphoid aggregates (defined as at least 20 closely aggregating cells) and alveolar inflammation evaluated as the number of macrophages in alveolar spaces increase with repetitive exposure to agricultural dust ( Ulu et al, 2021b ). The 2-3-fold increase in the number of BALF leukocytes following repetitive exposure to DE was reflected in approximately two fold increase in histopathological scores.…”

“…We have recently assessed the efficacy of dietary supplementation with the ω-3 PUFA docosahexaenoic acid (DHA) on altering the lung inflammatory response and recovery following acute and repetitive organic dust exposure ( Nordgren et al, 2014 ; Dominguez et al, 2020 ; Ulu et al, 2021a ). Mice were fed a mouse chow supplemented with DHA for four consecutive weeks prior to challenge with a single DE exposure (acute model) or DE challenge over 3 weeks (repetitive model).…”

“…In these investigations, we identified impacts of a high DHA diet on lung inflammation, including alterations in macrophage activation, that were overall protective against the deleterious impacts of DE exposure. However, these studies were limited in that they only assessed the impacts of one ω-3 PUFA, DHA, on male sex and on a limited dietary regimen of 4–7 weeks ( Dominguez et al, 2020 ; Ulu et al, 2021a ). Sex-specific differences in respiratory symptoms are observed among the asthmatic individuals and agricultural workers with asthma being more common in women than men and respiratory symptoms being more prevalent in men than women among the farmers ( CDC, 2019 ; Fix et al, 2020 ).…”