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

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.

Estrogen contributes to sex differences in M2a macrophages during multi‐walled carbon nanotube‐induced respiratory inflammation

“…However, the mechanism through which ER's promote the M2a phenotype has yet to be defined. New research highlights the importance of lipid mediators in lung inflammation 74–81 and some publications have even examined their role in a sex‐based manner 82–86 …”

“…New research highlights the importance of lipid mediators in lung inflammation [74][75][76][77][78][79][80][81] and some publications have even examined their role in a sex-based manner. [82][83][84][85][86] It has been reported that cysteinyl leukotriene (cysLT) biosynthesis is crucial for eosinophil recruitment to the airways following MWCNT exposure. 87 However, this mechanism was not investigated using a sex-based approach.…”

Psilocybe cubensis extract potently prevents fear memory recall and freezing behavior in short- but not long-term in a rat model of posttraumatic stress disorder.

“…Due to the limitation of mushroom extract and its cultivation period, and the number of study groups, we were able to use six rats in each experimental group. Although there are previous studies that used six or a smaller number of rats in each group for three-way ANOVA (Staiculescu et al, 2018; Ulu et al, 2022; Uno et al, 2020; see Statistical Analyses section). Third, to completely prove PTSD-related behaviors, other behavioral tests like acoustic startle response are needed, while we only used fear-conditioning apparatus.…”

“…Although, the statistical analyses have been done using SPSS software and the results are accurate, but a larger number of samples can give more credibility to the statistical results. Also, there are previous studies that used six or a smaller number of rats in each group for three-way ANOVA (Staiculescu et al, 2018; Ulu et al, 2022; Uno et al, 2020). Due to the limitation of mushroom extract and its cultivation period, and the number of study groups, we were able to use six rats in each experimental group.…”

Lipid-Sensing Receptor FFAR4 Modulates Pulmonary Epithelial Homeostasis following Immunogenic Exposures Independently of the FFAR4 Ligand Docosahexaenoic Acid (DHA)

“…Samples were prepared with the Mouse Immunology V2 code set from NanoString per the manufacturer’s protocols, hybridized for 16 h, and left in the final 4 C cycle for no longer than 30 min. The nCounter ® runs were completed per manufacturer instructions using an nCounter ® SPRINT Profiler, with an N of at least 3 per group and as previously published [ 97 ]. Normalization was completed using nSolver 4.0 Data Analysis software with default settings, except that the background thresholding was set to 30 for these analyses.…”