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The knee joint facilitates movement essential for daily activities. Its intricate anatomy makes it particularly prone to injury, specifically to the anterior cruciate ligament (ACL). ACL injury is a leading cause of post-traumatic osteoarthritis (PTOA), a degenerative joint disease that affects millions and results in pain, decreased mobility, and reduced quality of life. The cascade of initial inflammatory activity triggered by ACL injury plays a critical role in the pathogenesis of PTOA, as elevated levels of pro-inflammatory cytokines and catabolic enzymes lead to ongoing joint damage and dysfunction. Omega-3 fatty acids, an essential component of our diet, have been demonstrated to exert protective effects on joint tissues by modulating inflammatory pathways and promoting tissue repair. Specifically, these fatty acids diminish the production of inflammatory cytokines and enhance the resolution of inflammation, thereby potentially reducing the progression of PTOA. Given the lack of effective preventative therapies for PTOA, there is a pressing need for strategies that target early inflammatory processes to slow disease progression. This review provides a comprehensive analysis of the mechanistic and biochemical pathways through which these fatty acids influence knee joint health, with a focus on their impact in PTOA. By investigating the roles of omega-3 fatty acids and their metabolites, eicosanoids and specialized pro-resolving mediators, we highlight the potential for a nutrition based therapeutic application in managing PTOA.

Dietary long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) and their pro-resolving metabolites are protective against atherosclerotic disease, and ameliorate systemic inflammatory conditions including lupus erythematosus, psoriasis, and bronchial asthma. Organic bioaerosol inhalation is a common and injurious hazard associated with agricultural occupations such as work in swine concentrated animal feeding operations (CAFOs) and is known to increase the risk for developing respiratory conditions such as asthma and COPD. Nearly all cells secrete membrane-bound vesicles (extracellular vesicles, EVs) that have the capacity to transmit protein, nucleic acid, and lipid signaling mediators between cells. Using a polymer-based isolation technique (ExoQuick, PEG) followed by ultracentrifugation, EVs were isolated from CAFO dust extracts, and were quantified and partially characterized. Here, we investigated the role of the n-3 PUFA docosahexaenoic acid (DHA) as a component of n-6 to n-3 PUFA mixtures used to recapitulate physiologically relevant dietary ratios in the resolution of inflammatory injury caused by exposure to EVs carried by agricultural organic dust in vitro. Primary human bronchial epithelial cells, fibroblasts and monocyte-derived macrophages were exposed to EVs isolated from swine CAFO dust. Cells were treated with mixtures of n-6 and n-3 PUFA during recovery from the EV-induced injury. CAFO dust extract (DE) was found to contain EVs that contributed significantly to the overall consequences of exposure to complete DE. DHA-rich PUFA ratios inhibited DE-derived EV-induced proinflammatory cytokine release dose-dependently. DHA-rich PUFA ratios also reversed the damaging effects of EVs on recellularization of lung matrix scaffolds, accelerated wound healing, and stimulated the release of pro-resolution mediators. These results underscore the importance of n-3 PUFA as anti-inflammatory compounds during recovery from EV-laden environmental dust exposure in the context of cellular responses in vitro , warranting future translational studies.

Despite the importance of n-3 fatty acids for health, intakes remain below recommended levels. The objective of this study was to provide an updated assessment of fish and n-3 fatty acid intake (i.e., eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and EPA+DHA) in the United States using the 2003–2014 National Health and Nutrition Examination Survey (NHANES) data (n = 45,347)). Over this survey period, toddlers, children, and adolescents (aged 1–19) had significantly lower n-3 fatty acid intake (p < 0.001) compared to adults and seniors, which remained significant after adjusting for caloric intake. Females demonstrated lower n-3 fatty acid intake than males (p < 0.001), with adult and senior women having significantly lower intakes compared to men in the same age categories (p < 0.001) after adjustment for energy intake. Women also consumed less fish than men (5.8 versus 6.1 servings/month, p < 0.001). The estimated intakes of n-3 fatty acids in pregnant women did not differ from non-pregnant women (p = 0.6 for EPA+DHA), although pregnant women reported consuming less high n-3 fatty acid-containing fish than non-pregnant women (1.8 versus 2.6 servings/month, p < 0.001). Our findings indicate that subgroups of the population may be at higher risk of n-3 fatty acid intakes below recommended levels.

Exposure of the lungs to particulate matter (i.e. dust, wildfire smoke, air pollution) places individuals at an increased risk for developing chronic respiratory disease. Recent work has demonstrated the efficacy of omega-3 fatty acids and their metabolites in promoting the resolution of prolonged inflammation, however a comprehensive understanding of how omega-3 fatty acid balance impacts immune cell populations and crosstalk remains undescribed. We developed a 17-marker, 14-color spectral flow cytometry method to characterize the immunophenotypic changes in the bronchoalveolar space and lung tissue following 14 days of repetitive organic dust exposure or PBS vehicle. The populations of immune cells were compared in C57BL/6 (WT) and a transgenic model of increased omega-3 fatty acid (Fat-1) mice. Histopathologic examination revealed no difference between WT and Fat-1 mice at baseline or following organic dust exposure. Immune cell makeup within the bronchoalveolar space and lung tissue differed between WT and Fat-1 mice, with and without organic dust exposure. Fat-1 mice demonstrated a monocyte-dominant response compared to WT in both the airway and the lung tissue. Intriguingly, this monocyte-dominance was more prominent in female Fat-1 mice in the lung tissue and male Fat-1 mice in the airway. This suggests that monocyte populations are preferentially loaded following organic dust exposure in the lung and airways as a result omega-3 fatty acid metabolite-linked resolution processes, and that sex-dependent factors in this immune response are pivotal to consider in therapeutic strategies aimed at mitigating disease.

Although there are many recognized health benefits for the consumption of omega-3 (n-3) long-chain polyunsaturated fatty acids (LCPUFA), intake in the United States remains below recommended amounts. This analysis was designed to provide an updated assessment of fish and n-3 LCPUFA intake (eicosapentaenoic (EPA), docosahexaenoic acid (DHA), and EPA+DHA) in the United States adult population, based on education, income, and race/ethnicity, using data from the 2003-2014 National Health and Nutrition Examination Survey (NHANES) (n = 44,585). Over this survey period, participants with less education and lower income had significantly lower n-3 LCPUFA intakes and fish intakes (p < 0.001 for all between group comparisons). N-3 LCPUFA intake differed significantly according to ethnicity (p < 0.001), with the highest intake of n-3 LCPUFA and fish in individuals in the “Other” category (including Asian Americans). Supplement use increased EPA + DHA intake, but only 7.4% of individuals consistently took supplements. Overall, n-3 LCPUFA intake in this study population was low, but our findings indicate that individuals with lower educational attainment and income are at even higher risk of lower n-3 LCPUFA and fish intake.

Pulmonary diseases alter lung mechanical properties, can cause loss of function, and necessitate use of mechanical ventilation, which can be detrimental. Investigations of lung tissue (local) scale mechanical properties are sparse compared to that of the whole organ (global) level, despite connections between regional strain injury and ventilation. We examine ex vivo mouse lung mechanics by investigating strain values, local compliance, tissue surface heterogeneity, and strain evolutionary behavior for various inflation rates and volumes. A custom electromechanical, pressure–volume ventilator is coupled with digital image correlation to measure regional lung strains and associate local to global mechanics by analyzing novel pressure–strain evolutionary measures. Mean strains at 5 breaths per minute (BPM) for applied volumes of 0.3, 0.5, and 0.7 ml are 5.0, 7.8, and 11.3%, respectively, and 4.7, 8.8, and 12.2% for 20 BPM. Similarly, maximum strains among all rate and volume combinations range 10.7%–22.4%. Strain values (mean, range, mode, and maximum) at peak inflation often exhibit significant volume dependencies. Additionally, select evolutionary behavior (e.g., local lung compliance quantification) and tissue heterogeneity show significant volume dependence. Rate dependencies are generally found to be insignificant; however, strain values and surface lobe heterogeneity tend to increase with increasing rates. By quantifying strain evolutionary behavior in relation to pressure–volume measures, we associate time‐continuous local to global mouse lung mechanics for the first time and further examine the role of volume and rate dependency. The interplay of multiscale deformations evaluated in this work can offer insights for clinical applications, such as ventilator‐induced lung injury. Topological strain contours for representative mouse at various inflation volumes and frequencies

Agriculture dust contains many organic immunogenic compounds, and organic dust exposure is strongly associated with the development of immune-mediated chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD). Chronic organic dust exposure from agriculture sources induces chronic lung inflammatory diseases and organic dust exposure has recently been linked to an increased risk of developing dementia. The cytokine interleukin-22 (IL-22) has been established as an important mediator in the resolution and repair of lung tissues. The omega-3 fatty acid metabolite aspirin-triggered Resolvin D1 (AT-RvD1) has shown efficacy in modulating the immune response in both pulmonary and neurological inflammation but has not been explored as a therapeutic in organic dust exposure-induced neuroinflammation. Investigating the link between IL-22 and AT-RvD1 may help in developing effective therapies for these immune-mediated diseases. We aimed to investigate the link between organic dust exposure and neuroinflammation, the role of IL-22 in the pulmonary and neurological immune response to organic dust exposure, and the immune-modulating therapeutic applications of AT-RvD1 in an IL-22 knock-out mouse model of organic dust exposure. C57BL/6J (WT) and IL-22 knock-out (KO) mice were repetitively exposed to aqueous agriculture organic dust extract (DE) 5 days per week for 3 weeks (15 total instillations) and treated with AT-RvD1 either once per week (3 total injections) or 5 times per week (15 total injections) for 3 weeks and allowed to recover for 3 days. We observed a significant pulmonary and neurological immune response to DE characterized by the development of inducible bronchus associated lymphoid tissue in the lung and gliosis in the frontal areas of the brain. We also observed that IL-22 knock-out increased pulmonary and neurological inflammation severity. Animals exposed to DE and treated with AT-RvD1 displayed reduced lung pathology severity and gliosis. Our data demonstrate that DE exposure contributes to neurological inflammation and that IL-22 is crucial to effective tissue repair processes. Our data further suggest that AT-RvD1 may have potential as a novel therapeutic for organic dust exposure-induced, immune-mediated pulmonary and neurological inflammation, improving outcomes of those with these diseases.

Background Exposure to organic dust causes detrimental airway inflammation. Current preventative and therapeutic measures do not adequately treat resulting disease, necessitating novel therapeutic interventions. Recently identified mediators derived from polyunsaturated fatty acids exhibit anti-inflammatory and pro-resolving actions. We tested the potential of one of these mediators, maresin-1 (MaR1), in reducing organic dust-associated airway inflammation. Methods As bronchial epithelial cells (BECs) are pivotal in initiating organic dust-induced inflammation, we investigated the in vitro effects of MaR1 on a human BEC cell line (BEAS-2B). Cells were pretreated for 1 hour with 0–200 nM MaR1, followed by 1–24 hour treatment with 5% hog confinement facility-derived organic dust extract (HDE). Alternatively, a mouse lung slice model was utilized in supportive cytokine studies. Supernatants were harvested and cytokine levels determined via enzyme-linked immunosorbent assays. Epithelial cell protein kinase C (PKC) isoforms α and ϵ, and PKA activities were assessed via radioactivity assays, and NFκB and MAPK-related signaling mechanisms were investigated using luciferase vector reporters. Results MaR1 dose-dependently reduced IL-6 and IL-8 production following HDE treatment of BECs. MaR1 also reduced HDE-stimulated cytokine release including TNF-α in a mouse lung slice model when given before or following HDE treatment. Previous studies have established that HDE sequentially activates epithelial PKCα and PKCϵ at 1 and 6 hours, respectively that regulated TNF-α, IL-6, and IL-8 release. MaR1 pretreatment abrogated these HDE-induced PKC activities. Furthermore, HDE treatment over a 24-hour period revealed temporal increases in NFκB, AP-1, SP-1, and SRE DNA binding activities, using luciferase reporter assays. MaR1 pretreatment did not alter the activation of NFκB, AP-1, or SP-1, but did reduce the activation of DNA binding at SRE. Conclusions These observations indicate a role for MaR1 in attenuating the pro-inflammatory responses of BECs to organic dust extract, through a mechanism that does not appear to rely on reduced NFκB, AP-1, or SP-1-related signaling, but may be mediated partly through SRE-related signaling. These data offer insights for a novel mechanistic action of MaR1 in bronchial epithelial cells, and support future in vivo studies to test MaR1’s utility in reducing the deleterious inflammatory effects of environmental dust exposures.

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.

Purpose of ReviewAgriculture environments contain a variety of inflammatory aerosols that may increase risk for lung inflammation and disease in exposed individuals. In addition, epidemiological studies have also identified protective effects of rural environments and farming exposures.Recent FindingsIn this review, we will discuss recent literature published since 2016 that investigates the impact of differing agricultural exposures on respiratory health.SummaryDiscussions include the impact of farming modernization, education, and personal protective equipment usage among workers, timing and duration in mediating lung health outcomes, and population studies investigating the association between exposure and risk for numerous lung diseases.