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

Arzu Ulu,Stefanie N Sveiven,Carissa Bravo,Tara M Nordgren,Jun Yang,Bruce D Hammock,Jalene V Velazquez,Abigail Burr

doi:10.3389/fphar.2021.785193

Abstract

In agriculture industries, workers are at increased risk for developing pulmonary diseases due to inhalation of agricultural dusts, particularly when working in enclosed confinement facilities. Agricultural dusts inhalation leads to unresolved airway inflammation that precedes the development and progression of lung disease. We have previously shown beneficial effects of the omega-3 polyunsaturated fatty acid (ω-3 PUFA) DHA in protecting against the negative inflammatory effects of repetitive dust exposure in the lung. Dietary manipulation of pulmonary disease risk is an attractive and timely approach given the contribution of an increased ω-6 to ω-3 PUFA ratio to low grade inflammation and chronic disease in the Western diet. To prevent any confounding factors that comes with dietary supplementation of ω-3 PUFA (different sources, purity, dose, and duration), we employed a Fat-1 transgenic mouse model that convert ω-6 PUFA to ω-3 PUFA, leading to a tissue ω-6 to ω-3 PUFA ratio of approximately 1:1. Building on our initial findings, we hypothesized that attaining elevated tissue levels of ω-3 PUFA would attenuate agricultural dust-induced lung inflammation and its resolution. To test this hypothesis, we compared wild-type (WT) and Fat-1 transgenic mice in their response to aqueous extracts of agricultural dust (DE). We also used a soluble epoxide hydrolase inhibitor (sEH) to potentiate the effects of ω-3 PUFA, since sEH inhibitors have been shown to stabilize the anti-inflammatory P450 metabolites derived from both ω-3 and ω-6 PUFA and promote generation of specialized pro-resolving lipid mediators from ω-3 PUFA. Over a three-week period, mice were exposed to a total of 15 intranasal instillations of DE obtained from swine confinement buildings in the Midwest. We observed genotype and sex-specific differences between the WT vs. Fat-1 transgenic mice in response to repetitive dust exposure, where three-way ANOVA revealed significant main effects of treatment, genotype, and sex. Also, Fat-1 transgenic mice displayed reduced lymphoid aggregates in the lung following DE exposure as compared to WT animals exposed to DE, suggesting improved resilience to the DE-induced inflammatory effects. Overall, our data implicate a protective role of ω-3 FA in the lung following repetitive dust exposure.

Highlights

Agricultural workers are at increased risk for developing various respiratory diseases including chronic bronchitis, asthma, and chronic obstructive pulmonary disease (COPD), due in part to exposure to respirable organic dusts associated with these environments (Von Essen and Romberger, 2003; Nordgren and Charavaryamath, 2018; Sigsgaard et al, 2020)
Since TPPU can stabilize the P450 metabolites derived from the ω-3 fatty acids, EPA and docosahexaenoic acid (DHA) and promote generation of specialized pro-resolving mediators (SPM), these data suggest that elevated ω-3 fatty acids could be stabilized with a soluble epoxide hydrolase inhibitor (sEH) inhibitor to contribute to the decrease in proinflammatory cell influx into the lung in male sex
We have previously shown that total number of lymphoid aggregates and alveolar inflammation evaluated as the number of macrophages in alveolar spaces increase with repetitive exposure to agricultural dust (Ulu et al, 2021b)

Summary

Introduction

Agricultural workers are at increased risk for developing various respiratory diseases including chronic bronchitis, asthma, and COPD, due in part to exposure to respirable organic dusts associated with these environments (Von Essen and Romberger, 2003; Nordgren and Charavaryamath, 2018; Sigsgaard et al, 2020). Individuals that work in concentrated animal feeding operations, such as those housing swine, have appreciably increased risk for negative lung health outcomes (Iversen and Dahl, 2000; Kirkhorn and Garry, 2000; Pedersen et al, 2000; May et al, 2012; Pavilonis et al, 2013; Guillien et al, 2016; Nordgren and Bailey, 2016; Nordgren and Charavaryamath, 2018). Individuals consuming a diet with a high ω-6: ω-3 PUFA ratio may be at increased risk for inadequate control of inflammatory processes, with increased substrate to produce pro-inflammatory lipid mediators and a dearth of substrate for the production of specialized pro-resolving mediators (SPM)

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Conclusion