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OBJECTIVE: Swine veterinarians are known to be at risk for respiratory symptoms and airflow obstruction. The present study reassessed the prevalence of respiratory complaints and pulmonary function abnormalities in swine veterinarians and sought to characterize their response to bronchodilators. METHODS: A cross-sectional study was conducted during the American Association of Swine Veterinarians annual meeting. Subjects completed a respiratory symptom and workplace exposure history questionnaire and spirometry. Subjects with airflow obstruction were assessed for a post-bronchodilator response with beta2 agonist administration. RESULTS: Participants included 58 veterinarians (mean age, 45.5 years). Work-related symptoms assessed by questionnaire included rhinitis symptoms (60.3%), cough and chest tightness (55.2%), and wheezing (35.1%). Airflow obstruction was detected in 11/58 (19%) of subjects by spirometry. Only 2/9 (22.2%) met American Thoracic Society criteria for reversibility with bronchodilator administration. CONCLUSIONS: Respiratory symptoms and airway obstruction remain common findings in swine veterinarians. Airflow obstruction was not consistently reversible with beta agonists, suggesting that swine barn exposure may be a risk factor for irreversible airflow obstruction. [ABSTRACT FROM AUTHOR]

Abstract Background Contagious Bovine Pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides, is widespread in sub-Saharan Africa. The current live vaccine T1/44 has limited efficacy and occasionally leads to severe side effects in the animals. A better understanding of the immune responses triggered by Mycoplasma mycoides subsp. mycoides and their role in disease progression will help to facilitate the design of a rational vaccine. Currently, knowledge of cytokines involved in immunity and immunopathology in CBPP is rather limited. The aim of this study was to characterize the in vivo plasma concentrations of the cytokines TNF-α, IFN-γ, IL-4, IL-10 and the overall role of CD4+ T cells in the development of cytokine levels during a primary infection. Plasma cytokine concentrations in two groups of cattle (CD4+ T cell-depleted and non-depleted cattle) experimentally infected with Mycoplasma mycoides subsp. mycoides were measured and their relationship to the clinical outcomes was investigated. Results Plasma cytokine concentrations varied between animals in each group. Depletion of CD4+ T cells did not induce significant changes in plasma levels of TNF-α, IL-4, and IL-10, suggesting a minor role of CD4+ T cells in regulation or production of the three cytokines during the time window of depletion (1-2 weeks post depletion). Unexpectedly, the IFN-γ concentrations were slightly, but statistically significantly higher in the depleted group (p < 0.05) between week three and four post infection. Three CD4+ T cell-depleted animals that experienced severe disease, had high levels of TNF-α and IFN-γ. Only one severely diseased non-depleted animal showed a high serum concentration of IL-4 post infection. Conclusions Comparison of most severely diseased animals, which had to be euthanized prior to the expected date, versus less severe diseased animals, irrespective of the depletion status, suggested that high TNF-α levels are correlated with more severe pathology in concomitance with high IFN-γ levels.

Efficacious therapeutic options capable of resolving inflammatory lung disease associated with environmental and occupational exposures are lacking. This study sought to determine the preclinical therapeutic potential of lung-delivered recombinant interleukin (IL)-10 therapy following acute organic dust exposure in mice. Here, C57BL/6J mice were intratracheally instilled with swine confinement organic dust extract (ODE) (12.5%, 25%, 50% concentrations) with IL-10 (1 μg) treatment or vehicle control intratracheally-administered three times: 5 hr post-exposure and then daily for 2 days. The results showed that IL-10 treatment reduced ODE (25%)-induced weight loss by 66% and 46% at Day 1 and Day 2 post-exposure, respectively. IL-10 treatment reduced ODE (25%, 50%)-induced lung levels of TNFα (-76%, -83% [reduction], respectively), neutrophil chemoattractant CXCL1 (-51%, -60%), and lavage fluid IL-6 (-84%, -89%). IL-10 treatment reduced ODE (25%, 50%)-induced lung neutrophils (-49%, -70%) and recruited CD11c int CD11b + monocyte-macrophages (-49%, -70%). IL-10 therapy reduced ODE-associated expression of antigen presentation (MHC Class II, CD80, CD86) and inflammatory (Ly6C) markers and increased anti-inflammatory CD206 expression on CD11c int CD11b + cells. ODE (12.5%, 25%)-induced lung pathology was also reduced with IL-10 therapy. In conclusion, the studies here showed that short-term, lung-delivered IL-10 treatment induced a beneficial response in reducing inflammatory consequences (that were also associated with striking reduction in recruited monocyte-macrophages) following acute complex organic dust exposure.

The objective of this study was to assess fibrinogen (FIB) co-modified with citrulline (CIT) and/or malondialdehyde-acetaldehyde (MAA) initiates macrophage-fibroblast interactions leading to extracellular matrix (ECM) deposition that characterizes rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Macrophages (Mϕ) were stimulated with native-FIB, FIB-CIT, FIB-MAA or FIB-MAA-CIT. Supernatants (SN) (Mϕ-SN [U-937-derived] or MϕP-SN [PBMC-derived]) or direct antigens were co-incubated with human lung fibroblasts (HLFs). Gene expression was examined using RT-PCR. ECM deposition was quantified using immunohistochemistry and Western blot; cell signaling mechanisms were delineated. PDGF-BB and TGF- were measured in macrophage supernatants and inhibition studies performed using Su16f and SB431542, respectively. HLF gene expression of CD36, COL6A3, MMP-9 , MMP-10 , MMP-12 was increased following stimulations with Mϕ-SN generated from modified FIB but not from direct antigens. HLF stimulated with MϕP-SN FIB-MAA-CIT derived from RA-ILD patients resulted in 4- to 30-fold increases in COL6A3 and MMP12 expression; up-regulation was greater in HLFs stimulated with MϕP-SN derived from RA-ILD vs. controls. HLF exposure to Mϕ-SN FIB-MAA-CIT increased types I/VI collagen deposition vs. all other Mϕ-SN groups and was greater than FIB-MAA-CIT stimulation. PDGF-BB and TGF- signaling had the highest concentrations identified in Mϕ-SN FIB-MAA-CIT and MϕP-SN FIB-MAA-CIT , particularly from RA-ILD-derived cells. PDGF-BB and TGF- inhibitors, alone and in combination, significantly reduced HLF-mediated ECM deposition from Mϕ-SN stimulations. These results show that co-modified fibrinogen activates macrophages to produce PDGF-BB and TGF-β that promotes an aggressive HLF phenotype characterized increased ECM deposition. These results suggest that targeting CIT and/or MAA modifications or downstream cellular signals could represent novel approaches to RA-ILD treatment.

Objective: Investigate the association between the MUC5B rs35705950 promoter variant and survival in RA-associated interstitial lung disease (RA-ILD)., Methods: We studied participants in the Veteran Affairs Rheumatoid Arthritis (VARA) registry with validated ILD diagnoses. Participants were followed until death or end of study period. The MUC5B rs35705950 promoter variant was measured using an Infinium genotyping array, assuming autosomal dominant inheritance. Survival and cause of death were determined from VA death records and the National Death Index. Associations of the MUC5B promoter variant with survival were tested in Cox regression models adjusting for potential confounders., Results: Among 263 participants with RA-ILD (mean age 69 years, 95% male, 73% white race, 85% smoking history), the MUC5B promoter variant was present in 33.5%. Mortality rate was similar between those with (12.2/100PY [95% CI: 9.4, 15.8]) and without (11.1/100PY [95% CI: 9.1, 13.5]) the variant. MUC5B status was not significantly associated with survival overall (aHR 0.97 [95% CI: 0.68, 1.37]) or when stratified by ILD pattern (clinical usual interstitial pneumonia [UIP] aHR 0.86 [95% CI: 0.55, 1.35]; clinical non-UIP aHR 1.15 [95% CI: 0.63, 2.09]). Further, MUC5B status was not significantly associated with respiratory-related (aHR 0.83 [95% CI: 0.42, 1.66]) or non-respiratory causes of death (aHR 1.08 [95% CI: 0.72, 1.62])., Conclusion: While associated with RA-ILD risk, the MUC5B promoter variant was not predictive of survival among RA-ILD patients in this multicentre cohort. Further studies are needed to identify other genetic and non-genetic prognostic factors in RA-ILD to inform disease management., (Published by Oxford University Press 2024.)

Background: Whereas differences in inducible laryngeal obstruction (ILO) presentation on the basis of age have been observed within pediatric populations, age-based differences in adult populations are lacking., Objective: To describe differences in ILO on the basis of age in adults., Methods: Patients aged older than 16 years with confirmed ILO (vocal cord adduction > 50% during inspiration) by means of provocation-challenge rhinolaryngoscopy by their treating allergist were included. An investigator-designed questionnaire was administered using Research Electronic Data Capture with corresponding medical data collection. χ 2 tests, Student's t tests, analysis of variance, Cochran-Armitage test for trend, and Fisher's exact test were used., Results: The median age of the 67 patients was 50 years. P values less than .05 were considered significant. Those aged younger than 50 years (n = 31; mean age 35.6 years) reported more symptoms vs age 50 years and older (n = 36; mean age 61.8 years), including shortness of breath at rest and exertion (84% vs 39%, 94% vs 72%), throat tightness (81% vs 50%), chest tightness (81% vs 47%), and difficulty getting air in (81% vs 56%). Those aged younger than 50 years had an increased history of anxiety (68% vs 33%), asthma (55% vs 31%), positive methacholine challenge (52% vs 22%), increasing triggers with time (87% vs 43%), higher Pittsburgh Vocal Cord Dysfunction Index Scores (6.9 vs 5.5), and inspiratory curve flattening (48% vs 24%). Additional age-based subdivisions confirmed significant trends with the lowest reported ILO characteristics and symptoms in those aged 65 years and older., Conclusion: A high index of suspicion for ILO should be maintained in older adults since they may report less typical ILO symptoms and anxiety associations that prompt ILO evaluation., Competing Interests: Disclosures Dr Poole has received research regents (no monies) from AstraZeneca. Dr Poole, Dr Van De Graaff, Dr May, Dr Rorie, and Ms Walenz are site recruiters for clinical studies for asthma, sinus disease, and urticaria for GlaxoSmithKline, AstraZeneca, Regeneron Pharmaceuticals, and CellDex Therapeutics. The remaining authors have no conflicts of interest to report., (Published by Elsevier Inc.)

Objective: Increased risk of occupational exposure to bioaerosols has long been recognized in livestock operations including dairy facilities. Spanning the inhalable fraction (0-100 μm), dairy bioaerosols comprise a wide variety of inflammatory components that deposit in the nasopharyngeal region. The resultant inflammatory response from bioaerosol exposure is likely driving the increased prevalence of respiratory disease observed in dairy workers. It is also thought the microbiome of the upper respiratory system may help mediate this inflammation. We investigated the viability of a low-cost hypertonic saline nasal rinse intervention in modulating inflammatory responses in bioaerosol exposed dairy workers and its impact on microbial diversity., Methods: Pre- and post-shift nasal rinses were administered and collected alongside full shift inhalable personal breathing zone (PBZ) samples for each participant for up to 5 consecutive days. Treatment group participants ( n  = 23) received hypertonic saline rinses while control group participants ( n  = 22) received normotonic saline rinses. Particulate matter (PM) and endotoxin concentrations were quantified from PBZ samples using gravimetric and enzymatic analytical methods, respectively. Pre- and post-shift rinses were analyzed for pro- and anti-inflammatory markers and microbial diversity using a multiplex assay and 16S rRNA sequencing, respectively., Results: PM and endotoxin concentrations were comparable between groups indicating similar exposures. Post-shift pro-inflammatory markers were significantly higher than pre-shift for IL-13 ( p = .047), IL-1β ( p  < .001), IL-6 ( p  < .001), IL-8 ( p  < .001), and TNF-α ( p  = .024). There was no evidence of a difference in log concentrations between intervention group or day among any of the measured inflammatory markers. Anti-inflammatory IL-10 concentrations increased across the 5 sample days, independent of treatment group suggesting tonicity may not be driving the change. However, this result was not significant ( p  = .217). Nasal microbiome alpha (within sample) and beta (between sample) diversity metrics did not differ significantly between group or day demonstrating no adverse washout intervention effects., Conclusion: This study provided encouraging results that warrant future research to further evaluate saline nasal rinses as a workplace intervention.

Objectives: Though interstitial lung disease (ILD) contributes to excess morbidity and mortality in rheumatoid arthritis (RA), RA-ILD pathogenesis remains incompletely defined. As intermediate, non-classical and suppressed CD14+ monocytes are expanded in RA-ILD, this study sought to characterize gene expression profiles of circulating monocytes in RA-ILD., Methods: Peripheral blood mononuclear cells were collected from patients with RA without lung disease (N = 5), RA-ILD (N = 5), idiopathic pulmonary fibrosis (IPF; N = 5), and controls without lung and autoimmune disease (N = 4). RNA was extracted from CD14+ isolated monocytes and subjected to transcriptional analysis of 1365 genes. Gene enrichment and pathway analyses were performed., Results: Unsupervised clustering grouped patients with RA-ILD together with IPF for myeloid innate genes. For fibrosis genes, patients with RA-ILD clustered independent of comparator groups. There were 103, 66, and 64 upregulated and 66, 14, and 25 downregulated genes for RA-ILD, RA, and IPF, vs controls, respectively. For RA-ILD, there was increased expression of genes involved in regulating inflammation and fibrosis (SOCS3, CECAM1, LTB4R2, CLEC7A, IRF7, PHYKPL, GBP5, RAPGEF), epigenetic modification (KDM5D, KMT2D, OGT), and macrophage activation. Top canonical pathways included macrophage differentiation-activation, IL-12, neuroinflammatory, glucocorticoid receptor, and IL-27 signalling., Conclusions: Circulating monocytes in RA-ILD patients demonstrate unique gene expression profiles with innate immune gene features more aligned with IPF as opposed to RA in the absence of clinical lung disease with fibrosis gene expression that was distinct from RA and IPF. These studies are important for understanding disease pathogenesis and may provide information for future therapeutic targets in RA-ILD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Environmental lipopolysaccharide (LPS) and microbial component-enriched organic dusts cause significant lung disease. These environmental exposures induce the recruitment and activation of distinct lung monocyte/macrophage subpopulations involved in disease pathogenesis. Aconitate decarboxylase 1 ( Acod1 ) was one of the most upregulated genes following LPS (vs. saline) exposure of murine whole lungs with transcriptomic profiling of sorted lung monocyte/macrophage subpopulations also highlighting its significance. Given monocyte/macrophage activation can be tightly linked to metabolism, the objective of these studies was to determine the role of the immunometabolic regulator ACOD1 in environmental exposure-induced lung inflammation., Methods: Wild-type (WT) mice were intratracheally (i.t.) instilled with 10 μg of LPS or saline. Whole lungs were profiled using bulk RNA sequencing or sorted to isolate monocyte/macrophage subpopulations. Sorted subpopulations were then characterized transcriptomically using a NanoString innate immunity multiplex array 48 h post-exposure. Next, WT and Acod1 -/- mice were instilled with LPS, 25% organic dust extract (ODE), or saline, whereupon serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected. BALF metabolites of the tricarboxylic acid (TCA) cycle were quantified by mass spectrometry. Cytokines/chemokines and tissue remodeling mediators were quantitated by ELISA. Lung immune cells were characterized by flow cytometry. Invasive lung function testing was performed 3 h post-LPS with WT and Acod1 -/- mice., Results: Acod1 -/- mice treated with LPS demonstrated decreased BALF levels of itaconate, TCA cycle reprogramming, decreased BALF neutrophils, increased lung CD4 + T cells, decreased BALF and lung levels of TNF-α, and decreased BALF CXCL1 compared to WT animals. In comparison, Acod1 -/- mice treated with ODE demonstrated decreased serum pentraxin-2, BALF levels of itaconate, lung total cell, neutrophil, monocyte, and B-cell infiltrates with decreased BALF levels of TNF-α and IL-6 and decreased lung CXCL1 vs. WT animals. Mediators of tissue remodeling (TIMP1, MMP-8, MMP-9) were also decreased in the LPS-exposed Acod1 -/- mice, with MMP-9 also reduced in ODE-exposed Acod1 -/- mice. Lung function assessments demonstrated a blunted response to LPS-induced airway hyperresponsiveness in Acod1 -/- animals., Conclusion: Acod1 is robustly upregulated in the lungs following LPS exposure and encodes a key immunometabolic regulator. ACOD1 mediates the proinflammatory response to acute inhaled environmental LPS and organic dust exposure-induced lung inflammation., Competing Interests: JP has received research reagent from AstraZeneca (no monies) and has been a site investigator for allergy and asthma clinical studies for Takeda, GlaxoSmithKline, Regeneron, Areteia, and AstraZeneca (no monies). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schwab, Nelson, Gleason, Schanze, Wyatt, Shinde, Xiao, Thomas, Guda, Bailey, Kielian, Thiele and Poole.)

Objective: The objective of this study is to determine the associations of protein-specific anti-malondialdehyde-acetaldehyde (MAA) antibodies with prevalent and incident rheumatoid arthritis-interstitial lung disease (RA-ILD)., Methods: Within a multicenter, prospective cohort of US veterans with RA, RA-ILD was validated by medical record review of clinical diagnoses, chest imaging, and pathology. Serum antibodies to MAA-albumin, MAA-collagen, MAA-fibrinogen, and MAA-vimentin (IgA, IgM, and IgG) were measured by a standardized enzyme-linked immunosorbent assay. Associations of anti-MAA antibodies with prevalent and incident RA-ILD were assessed using multivariable regression models adjusting for established RA-ILD risk factors., Results: Among 2,739 participants with RA (88% male, mean age of 64 years), there were 114 with prevalent and 136 with incident RA-ILD (average time to diagnosis: 6.6 years). Higher IgM anti-MAA-collagen (per 1 SD: adjusted odds ratio [aOR] 1.28, 95% confidence interval [CI] 1.02-1.61), IgA anti-MAA-fibrinogen (aOR 1.48, 95% CI 1.14-1.92), and IgA (aOR 1.78, 95% CI 1.34-2.37) and IgG (aOR 1.48, 95% CI 1.14-1.92) anti-MAA-vimentin antibodies were associated with prevalent RA-ILD. In incident analyses, higher IgA (per one SD: adjusted hazards ratio [aHR] 1.40, 95% CI 1.11-1.76) and IgM (aHR 1.29, 95% CI 1.04-1.60) anti-MAA-albumin antibody concentrations were associated with increased ILD risk. Participants with IgA (aHR 2.13, 95% CI 1.16-3.90) or IgM (aHR 1.98, 95% CI 1.08-3.64) anti-MAA-albumin antibody concentrations in the highest quartile had an approximately two-fold increased risk of incident RA-ILD. Across all isotypes, anti-MAA-fibrinogen, anti-MAA-collagen, and anti-MAA-vimentin antibodies were not significantly associated with incident RA-ILD., Conclusion: Protein-specific anti-MAA antibodies to collagen, fibrinogen, and vimentin were associated with prevalent RA-ILD. IgA and IgM anti-MAA-albumin antibodies were associated with a higher risk of incident RA-ILD. These findings suggest that MAA modifications and resultant immune responses may contribute to RA-ILD pathogenesis., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Organic dusts are complex bioaerosol mixtures comprised of dust and par ticulate matter of organic origin. These include components from bacteria, fungi, pollen, and viruses to fragments of animals and plants commonplace to several environmental/occupational settings encompassing agriculture/farming, grain processing, waste/recycling, textile, cotton, woodworking, bird breeding, and more. Organic dust exposures are linked to development of chronic bronchitis, chronic obstructive pulmonary disease, asthma, asthma-like syndrome, byssinosis, hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. Risk factors of disease development include cumulative dust exposure, smoking, atopy, timing/duration, and nutritional factors. The immunopathogenesis predominantly involves Toll-like receptor signaling cascade, T-helper 1/T-helper 17 lymphocyte responses, neutrophil influx, and potentiation of manifestations associated with allergy. The true prevalence of airway disease directly attributed to organic dust, especially in a workplace setting, remains challenging. Diagnostic confirmation can be difficult and complicated by hesitancy from workers to seek medical care, driven by fears of potential labor-related consequence. Clinical respiratory and systemic presentations coupled with allergy testing, lung function patterns of obstructive versus restrictive disease, and radiological characteristics are typically utilized to delineate these various organic dust-associated respiratory diseases. Prevention, risk reduction, and management primarily focus on reducing exposure to the offending dust, managing symptoms, and preventing disease progression., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Agricultural workers exposed to organic dust from swine concentrated animal feeding operations (CAFOs) have increased chances of contracting chronic lung disease. Mucociliary clearance represents a first line of defense against inhaled dusts, but organic dust extracts (ODEs) from swine barns cause cilia slowing, leading to decreased bacterial clearance and increased lung inflammation. Because nutritional zinc deficiency is associated with chronic lung disease, we examined the role of zinc supplementation in ODE-mediated cilia slowing. Ciliated mouse tracheal epithelial cells were pretreated with 0-10 µg/mL ZinPro TM for 1 h, followed by treatment with 5% ODE for 24 h. Cilia beat frequency (CBF) and protein kinase C epsilon (PKCε) activity were assayed. ODE treatment resulted in cilia slowing after 24 h, which was reversed with 0.5 and 1.0 µg/mL ZinPro pre-treatment. No zinc protection was observed at 50 ng/mL, and ciliated cells detached at high concentrations (100 µg/mL). ZinPro alone produced no changes in the baseline CBF and showed no toxicity to the cells at concentrations of up to 10 µg/mL. Pre-treatment with ZinPro inhibited ODE-stimulated PKCε activation in a dose-dependent manner. Based on ZinPro's superior cell permeability compared to zinc salts, it may be therapeutically more effective at reversing ODE-mediated cilia slowing through a PKCε pathway. These data demonstrate that zinc supplementation may support the mucociliary transport apparatus in the protection of CAFO workers against dust-mediated chronic lung disease., Competing Interests: JAP received research regents (anti-IL-33/ST2 blocking antibody reagent, no money) from AstraZeneca, and JAP serves as a site recruiter for clinical industry studies for asthma, sinus disease, and urticaria (GlaxoSmithKline, AstraZeneca, Regeneron Pharmaceuticals, CellDex Therapeutics). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs. The funders had no role in study design, data collection, and analysis; in the decision to publish the article; in the preparation of the manuscript; or in the decision to publish the results. The authors alone are responsible for the content of this manuscript.

Objectives: To quantify associations of serum alarmins with risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD)., Methods: Using serum collected at enrolment, three alarmins (IL-33, thymic stromal lymphopoietin [TSLP] and IL-25) were measured in a multicentre prospective RA cohort. ILD was classified using systematic medical record review. Cross-sectional associations of log-transformed (IL-33, TSLP) or quartile (IL-25) values with RA-ILD at enrolment (prevalent RA-ILD) were examined using logistic regression, while associations with incident RA-ILD developing after enrolment were examined using Cox proportional hazards. Covariates in multivariate models included age, sex, race, smoking status, RA disease activity score and anti-cyclic citrullinated antibody positivity., Results: Of 2835 study participants, 115 participants (4.1%) had prevalent RA-ILD at baseline and an additional 146 (5.1%) developed incident ILD. There were no associations between serum alarmin concentrations and prevalent ILD in unadjusted or adjusted logistic regression models. In contrast, there was a significant inverse association between IL-33 concentration and the risk of developing incident RA-ILD in unadjusted (hazard ratio [HR] 0.73 per log-fold increase; 95% CI: 0.57, 0.95; P = 0.018) and adjusted (HR 0.77; 95% CI: 0.59, 1.00; P = 0.047) models. No significant associations of TSLP or IL-25 with incident ILD were observed., Conclusion: In this study, we observed a significant inverse association between serum IL-33 concentration and the risk of developing incident RA-ILD, but no associations with prevalent ILD. Additional investigation is required to better understand the mechanisms driving this relationship and how serum alarmin IL-33 assessment might contribute to clinical risk stratification in patients with RA., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Many vulnerable people lose their health or lives each year as a result of unhealthy environmental conditions that perpetuate medical conditions within the scope of allergy and immunology specialists' expertise. While detrimental environmental factors impact all humans globally, the effect is disproportionately more profound in impoverished neighborhoods. Environmental injustice is the inequitable exposure of disadvantaged populations to environmental hazards. Professional medical organizations such as the American Academy of Allergy, Asthma & Immunology (AAAAI) are well positioned to engage and encourage community outreach volunteer programs to combat environmental justice. Here we discuss how environmental injustices and climate change impacts allergic diseases among vulnerable populations. We discuss pathways allergists/immunologists can use to contribute to addressing environmental determinants by providing volunteer clinical service, education, and advocacy. Furthermore, allergists/immunologists can play a role in building trust within these communities, partnering with other patient advocacy nonprofit stakeholders, and engaging with local, state, national, and international nongovernmental organizations, faith-based organizations, and governments. The AAAAI's Volunteerism Addressing Environmental Disparities in Allergy (VAEDIA) is the presidential task force aiming to promote volunteer initiatives by creating platforms for discussion and collaboration and by funding community-based projects to address environmental injustice., Competing Interests: Disclosure statement Disclosure of potential conflict of interest: M. Mahdavinia reports research support from the National Institutes of Health (NIH), Food Allergy Research and Education (FARE), Optinose Foundation, Brinson Foundation, and Institute for Translation Medicine in Chicago. J. A. Poole receives funding from the Department of Defense and the National Institute of Occupational Safety and Health; has received research regents from AstraZeneca; and acts as site principal investigator (PI) for clinical studies for asthma, sinus disease, and urticaria involving GlaxoSmithKline, AstraZeneca, Regeneron Pharmaceuticals, and CellDex Therapeutics. A. J. Apter receives research support from the NIH and the Patient-Centered Outcomes Research Institute. A. A. Pappalardo has served on the medical advisory board for Takeda, Eli Lilly, and Sanofi Regeneron; has received grant funding from the NIH, Agency for Health Research and Quality, and FARE; and has acted as a consultant for Optum/United Health Group. E. C. Matsui has received research support from the NIH. J. A. Bernstein is site PI and consultant for Sanofi Regeneron, AstraZeneca, GSK, Novartis, Genentech, Biocryst, Pharming, Takeda, CSL Behring, Ionis, Biomarin, Blueprint Medicine, Cogent, Celldex, Escient, Jasper Pharmaceuticals, Amgen, Kalvista, and Pharvaris; is president of American Academy of Allergy, Asthma & Immunology (AAAAI), World Allergy Organization, and Interasma; and Hereditory Angioedema medical advisory board. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA)., Methods: Within a multicenter, prospective cohort of US veterans with RA, we performed a cross-sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP-1, 3, 7, and 9 concentrations were measured in plasma samples, then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA-ILD risk factors., Results: Among 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person-years of follow-up (crude incidence rate 7.5/1,000 person-years). Participants with the highest quartile of MMP-7 concentrations had a nearly four-fold increased odds of prevalent ILD (adjusted odds ratio 3.78 [95% confidence interval (95% CI) 1.86-7.65]) and over two-fold increased risk of incident ILD (adjusted hazard ratio 2.33 [95% CI 1.35-4.02]). Higher MMP-9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r = -0.30, P = 0.005)., Conclusion: MMP-7 and MMP-9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA-ILD risk factors. These population-level findings further support a potential pathogenic role for MMPs in RA-ILD and suggest that their measurement could facilitate RA-ILD risk stratification., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Environmental/occupational exposures cause significant lung diseases. Agricultural organic dust extracts (ODE) and bacterial component lipopolysaccharide (LPS) induce recruited, transitioning murine lung monocytes/macrophages, yet their cellular role remains unclear., Methods: CCR2 RFP + mice were intratracheally instilled with high concentration ODE (25%), LPS (10 μg), or gram-positive peptidoglycan (PGN, 100 μg) for monocyte/macrophage cell-trafficking studies. CCR2 knockout (KO) mice and administration of intravenous clodronate liposomes strategies were employed to reduce circulating monocytes available for lung recruitment following LPS exposure. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected. Pro-inflammatory and/or pro-fibrotic cytokines, chemokines, and lung extracellular matrix mediators were quantitated by ELISA. Infiltrating lung cells including monocyte/macrophage subpopulations, neutrophils, and lymphocytes were characterized by flow cytometry. Lung histopathology, collagen content, vimentin, and post-translational protein citrullination and malondialdehyde acetaldehyde (MAA) modification were quantitated. Parametric statistical tests (one-way ANOVA, Tukey'smultiple comparison) and nonparametric statistical (Kruskal-Wallis, Dunn's multiple comparison) tests were used following Shapiro-Wilk testing for normality., Results: Intratracheal instillation of ODE, LPS, or PGN robustly induced the recruitment of inflammatory CCR2 + CD11c int CD11b hi monocytes/macrophages and both CCR2 + and CCR2 - CD11c - CD11b hi monocytes at 48 h. There were also increases in CCR2 + CD4 + and CD8 + T cells and NK cells. Despite reductions in LPS-induced lung infiltrating CD11c int CD11b hi cells (54% reduction), CCR2 knockout (KO) mice were not protected against LPS-induced inflammatory and pro-fibrotic consequences. Instead, compensatory increases in lung neutrophils and CCL2 and CCL7 release occurred. In contrast, the depletion of circulating monocytes through the administration of intravenous clodronate (vs. vehicle) liposomes 24 h prior to LPS exposure reduced LPS-induced infiltrating CD11c int CD11b hi monocyte-macrophage subpopulation by 59% without compensatory changes in other cell populations. Clodronate liposome pre-treatment significantly reduced LPS-induced IL-6 (66% reduction), matrix metalloproteinases (MMP)-3 (36%), MMP-8 (57%), tissue inhibitor of metalloproteinases (61%), fibronectin (38%), collagen content (22%), and vimentin (40%). LPS-induced lung protein citrullination and MAA modification, post-translational modifications implicated in lung disease, were reduced (39% and 48%) with clodronate vs. vehicle liposome., Conclusion: Highly concentrated environmental/occupational exposures induced the recruitment of CCR2 + and CCR2 - transitioning monocyte-macrophage and monocyte subpopulations and targeting peripheral monocytes may reduce the adverse lung consequences resulting from exposures to LPS-enriched inhalants., (© 2024. The Author(s).)

Respiratory-related diseases are a leading cause of death in rheumatoid arthritis (RA) and are disproportionately higher in men, which may be attributable to environmental risk factors. Animal studies have demonstrated potentiated autoimmunity, arthritis, and profibrotic/inflammatory lung disease with a combination of airborne exposures and collagen-induced arthritis (CIA). This study aimed to determine whether hormone-dependent differences explained these observations. Arthritis-prone male intact and castrated DBA/1J mice received intranasal inhalation of lipopolysaccharide (LPS) daily for 5 wk and CIA induction. Arthritis scores and serum pentraxin-2 levels were increased in castrated versus intact mice. In contrast, airway cell influx, lung tissue infiltrates, and lung levels of proinflammatory and profibrotic markers (C5a, IL-33, and matrix metalloproteinases) were reduced in castrated versus intact mice. CIA + LPS-induced lung histopathology changes and the expression of lung autoantigens including malondialdehyde acetaldehyde (MAA)- and citrulline (CIT)-modified proteins and vimentin were reduced in castrated animals. There were no differences in serum anti-MAA or anti-CIT protein antibody (ACPA) levels or serum pentraxin levels between groups. Testosterone replacement led to a reversal of several lung inflammatory/profibrotic endpoints noted earlier in castrated male CIA + LPS-treated mice with testosterone supplementation promoting neutrophil influx, MAA expression, and TNF-α, IL-6, and MMP-9. These findings imply that testosterone contributes to lung and arthritis inflammatory responses following CIA + LPS coexposure, but not to systemic autoantibody responses. The CIA + LPS model provides a paradigm for investigations focused on the mechanistic underpinnings for epidemiologic and phenotypic sex differences in RA-related lung disease. NEW & NOTEWORTHY Our study shows that testosterone acts as a key immunomodulatory hormone contributing to critical features of rheumatoid arthritis (RA)-associated lung disease in the setting of airborne endotoxin (lipopolysaccharide; LPS) exposures and concomitant arthritis induction in mice. The exaggerated airway inflammation observed following combined exposures in male mice was accompanied by increases in profibrotic mediators, netosis, and increased expression of lung autoantigens, all relevant to the pathogenesis of lung disease in arthritis.

The objective of this article is to review recent literature on the implications of extreme weather events such as thunderstorms, wildfires, tropical cyclones, freshwater flooding, and temperature extremes in relationship to asthma symptoms. Several studies have shown worsening of asthma symptoms with thunderstorms, wildfires, tropical cyclones, freshwater flooding, and temperature extremes. In particular, thunderstorm asthma can be exacerbated by certain factors such as temperature, precipitation, and allergen sensitization. Therefore, it is imperative that the allergy and immunology community be aware of the health effects associated with these extreme weather events in order to educate patients and engage in mitigation strategies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Interstitial lung disease (ILD) is associated with significant mortality in rheumatoid arthritis (RA) patients with key cellular players remaining largely unknown. This study aimed to characterize inflammatory and myeloid derived suppressor cell (MDSC) subpopulations in RA-ILD as compared to RA, idiopathic pulmonary fibrosis (IPF) without autoimmunity, and controls., Methods: Peripheral blood was collected from patients with RA, RA-ILD, IPF, and controls (N = 60, 15/cohort). Myeloid cell subpopulations were identified phenotypically by flow cytometry using the following markers:CD45,CD3,CD19,CD56,CD11b,HLA-DR,CD14,CD16,CD15,CD125,CD33. Functionality of subsets were identified with intracellular arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS) expression., Results: There was increased intermediate (CD14 ++ CD16 + ) and nonclassical (CD14 +/- CD16 ++ ) and decreased classical (CD14 ++ CD16 - ) monocytes in RA, RA-ILD, and IPF vs. control. Intermediate monocytes were higher and classical monocytes were lower in RA-ILD vs. RA but not IPF. Monocytic (m)MDSCs were higher in RA-ILD vs. control and RA but not IPF. Granulocytic (g)MDSCs did not significantly differ. In contrast, neutrophils were increased in IPF and RA-ILD patients with elevated expression of Arg-1 sharing similar dimensional clustering pattern. Eosinophils were increased in RA-ILD vs. controls, RA and IPF. Across cohorts, iNOS was decreased in intermediate/nonclassical monocytes but increased in mMDSCs vs. classical monocytes. In RA-ILD, iNOS positive mMDSCs were increased versus classic monocytes., Conclusions: Myeloid cell subpopulations are significantly modulated in RA-ILD patients with expansion of CD16 + monocytes, mMDSCs, and neutrophils, a phenotypic profile more aligned with IPF than other RA patients. Eosinophil expansion was unique to RA-ILD, potentially facilitating disease pathogenesis and providing a future therapeutic target., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Although clinical and genetic risk factors have been identified for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), there are no current tools allowing for risk stratification. We sought to develop and validate an ILD risk model in a large, multicentre, prospective RA cohort., Methods: Participants in the Veterans Affairs RA (VARA) registry were genotyped for 12 single nucleotide polymorphisms (SNPs) associated with idiopathic pulmonary fibrosis. ILD was validated through systematic record review. A genetic risk score (GRS) was computed from minor alleles weighted by effect size with ILD, using backward selection. The GRS was combined with clinical risk factors within a logistic regression model. Internal validation was completed using bootstrapping, and model performance was assessed by the area under the receiver operating curve (AUC)., Results: Of 2,386 participants (89% male, mean age 69.5 years), 9.4% had ILD. Following backward selection, five SNPs contributed to the GRS. The GRS and clinical factors outperformed clinical factors alone in discriminating ILD (AUC 0.675 vs 0.635, p< 0.001). The shrinkage-corrected performance for combined and clinical-only models was 0.667 (95% CI 0.628, 0.712) and 0.623 (95% CI 0.584, 0.651), respectively. Twenty percent of the cohort had a combined risk score below a cut-point with >90% sensitivity., Conclusion: A clinical and genetic risk model discriminated ILD in a large, multicentre RA cohort better than a clinical-only model, excluding 20% of the cohort from low-yield testing. These results demonstrate the potential utility of a GRS in RA-ILD and support further investigation into individualized risk stratification and screening., (Published by Oxford University Press 2024.)

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo , the surfactant protein C protein (SPC) Cre + embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre + , MyD88 floxed, were also developed. Using an established protocol, mice were intranasally instilled with ODE or saline once or daily up to 3 weeks. Mice with MyD88-deficient SPC + lung epithelial cells exhibited decreased neutrophil influx following ODE exposure once and repetitively for 1 week without modulation of classic pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and neutrophil chemoattractants. This protective response was lost after 3 weeks of repetitive exposure. ODE-induced Muc5ac mucin expression at 1 week was also reduced in MyD88-deficient SPC + cells. Acute ODE-induced IL-33 was reduced in MyD88-deficient SPC + cells whereas serum IgE levels were increased at one week. In contrast, mice with inducible MyD88-deficient CCSP + airway epithelial cells demonstrated no significant difference in experimental indices following ODE exposure. Collectively, these findings suggest that MyD88-dependent signaling targeted to all airway epithelial cells plays an important role in mediating neutrophil influx and mucin production in response to acute organic dust exposures.

Little is known about the inflammatory potential of diet and its relation to bone health. This cross-sectional study examined the association between the inflammatory potential of diet and bone-related outcomes in midwestern, post-menopausal women enrolled in the Heartland Osteoporosis Prevention Study (HOPS) randomized controlled trial. Dietary intake from the HOPS cohort was used to calculate Dietary Inflammatory Index (DII ® ) scores, which were energy-adjusted (E-DII TM ) and analyzed by quartile. The association between E-DII and lumbar and hip bone mineral density (BMD) and lumbar trabecular bone scores (TBS; bone structure) was assessed using ANCOVA, with pairwise comparison to adjust for relevant confounders (age, education, race/ethnicity, smoking history, family history of osteoporosis/osteopenia, BMI, physical activity, and calcium intake). The cohort included 272 women, who were predominately white (89%), educated (78% with college degree or higher), with a mean BMI of 27 kg/m 2 , age of 55 years, and E-DII score of -2.0 ± 1.9 (more anti-inflammatory). After adjustment, E-DII score was not significantly associated with lumbar spine BMD ( p = 0.53), hip BMD ( p = 0.29), or TBS at any lumbar location ( p > 0.05). Future studies should examine the longitudinal impact of E-DII scores and bone health in larger, more diverse cohorts.

Purpose of Review: Occupational rhinitis is an underdiagnosed disease with significant morbidity and implications in the workplace. Multiple factors associated with this disease continue to pose a challenge to investigators. This review aims to summarize recent literature in occupational rhinitis, including classifications, pathogenesis, diagnosis, and treatment, as well as the impact of occupational rhinitis on individuals. Additionally, it identifies areas in need of further research and investigation., Recent Findings: We highlight current research on the association between occupational rhinitis and occupational asthma and the role of immunotherapy in this disease. Discussion includes the impact of social trends on workers and the wider consequences of occupational rhinitis including decreased work productivity, absenteeism, and socioeconomic burden. Occupational rhinitis remains a challenging disease entity due to the numerous potential causative factors, reduced recognition, morbidity in asthma, and therapeutic limitations. Additional research is needed to better identify disease predictors and develop effective management strategies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Occupational lung disease, including asthma, is a significant cause of disability worldwide. The dose, exposure frequency, and nature of the causal agent influence the inflammatory pathomechanisms that inform asthma disease phenotype and progression. While surveillance, systems engineering, and exposure mitigation strategies are essential preventative considerations, no targeted medical therapies are currently available to ameliorate lung injury post-exposure and prevent chronic airway disease development., Recent Findings: This article reviews contemporary understanding of allergic and non-allergic occupational asthma mechanisms. In addition, we discuss the available therapeutic options, patient-specific susceptibility and prevention measures, and recent scientific advances in post-exposure treatment conception. The course of occupational lung disease that follows exposure is informed by individual predisposition, immunobiologic response, agent identity, overall environmental risk, and preventative workplace practices. When protective strategies fail, knowledge of underlying disease mechanisms is necessary to inform targeted therapy development to lessen occupational asthma disease severity and occurrence., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Biomarkers have been proposed as tools to aid in the identification and prognostication of interstitial lung disease (ILD) in rheumatoid arthritis (RA). We performed a systematic review of studies evaluating peripheral blood biomarkers and their association with RA-ILD and its prognosis., Methods: Medline, Embase, the Cochrane Library, and Scopus were queried for relevant studies, with the final search update on July 12, 2021. We included studies evaluating peripheral blood biomarkers for the identification and/or prognostication of RA-ILD, extracting the performance of individual biomarkers for identifying RA-ILD, and predicting prognosis. Modified versions of the Quality Assessment of Diagnostic Accuracy Studies 2 and the Quality in Prognosis Studies tools were used for quality assessment., Results: Seventy studies met eligibility criteria. Study and patient characteristics, analytical methods, strength and consistency of associations, and study quality were heterogeneous. A total of 92 biomarkers were positively associated and 12 were negatively associated with RA-ILD among patients with RA in one or more report. Only a small number of biomarkers were evaluated in multiple cohorts using adjusted analyses. Biomarkers most strongly associated with RA-ILD overlapped with those identified for idiopathic pulmonary fibrosis. Few prognostic biomarkers of RA-ILD were identified., Conclusion: Several peripheral blood biomarkers are associated with the presence of RA-ILD, but few have been assessed in multivariable models, have been externally validated, have discriminated RA-ILD from other lung disease, or have prognosticated the disease course. High-quality studies investigating and validating peripheral biomarkers in RA-ILD are needed before they can be employed in clinical care., (© 2023 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Attributes defining the Social Determinants of Health (SDoH) are associated with disproportionate exposures to environmental hazards and differential health outcomes among communities. The dynamics between SDoH, disproportionate environmental exposures, and differential health outcomes are often specific to micro-geographic areas., Methods: This study focused on children less than 20 years of age who lived in Douglas County, Nebraska, during 2016-2019. To assess the role of SDoH in differential exposures, we evaluated the association between SDoH metrics and criteria pollutant concentrations and the association between SDoH and pediatric asthma exacerbations to quantify the role of SDoH in differential pediatric asthma outcomes. The Bayesian Poisson regression model with spatial random effects was used to evaluate associations., Results: We identified significant positive associations between the annual mean concentration of criteria pollutants (carbon monoxide, particulate matter 2.5 , nitrogen dioxide, sulfur dioxide) with race (Non-Hispanic Black and Hispanic/Latino), financial stability, and literacy. Additionally, there were significant positive associations between higher rates of pediatric asthma emergency department visits and neighborhoods with more Non-Hispanic Black children, children without health insurance coverage, and households without access to a vehicle., Conclusions: Non-Hispanic Black and Hispanic/Latino children living in Douglas County, NE experience disproportionately higher exposure to criteria pollutant concentrations. Additionally, higher rates of asthma exacerbations among Non-Hispanic Black children could be due to reduced access to respiratory care that is potentially the result of financial instability and vehicle access. These results could inform city planners and health care providers to mitigate respiratory risks among these higher at-risk populations., (© 2023. The Author(s).)

Rationale: Asthma is a chronic airway condition that occurs more often in women than men during reproductive years. Population studies have collectively shown that long-term use of oral contraceptives decreased the onset of asthma in women of reproductive age. In the current study, we hypothesized that steady-state levels of estrogen would reduce airway inflammation and airway hyperresponsiveness to methacholine challenge., Methods: Ovariectomized BALB/c mice (Ovx) were implanted with subcutaneous hormone pellets (estrogen, OVX-E2) that deliver consistent levels of estrogen [68 ± 2 pg/mL], or placebo pellets (OVX-Placebo), followed by ovalbumin sensitization and challenge. In conjunction with methacholine challenge, immune phenotyping was performed to correlate inflammatory proteins and immune populations with better or worse pulmonary outcomes measured by invasive pulmonary mechanics techniques., Results: Histologic analysis showed an increase in total cell infiltration and mucus staining around the airways leading to an increased inflammatory score in ovarectomized (OVX) animals with steady-state estrogen pellets (OVX-E2-OVA) as compared to other groups including female-sham operated (F-INTACT-OVA) and OVX implanted with a placebo pellet (OVX-Pl-OVA). Airway resistance (Rrs) and lung elastance (Ers) were increased in OVX-E2-OVA in comparison to F-INTACT-OVA following aerosolized intratracheal methacholine challenges. Immune phenotyping revealed that steady-state estrogen reduced CD3+ T cells, CD19+ B cells, ILC2 and eosinophils in the BAL across all experiments. While these commonly described allergic cells were reduced in the BAL, or airways, we found no changes in neutrophils, CD3+ T cells or CD19+ B cells in the remaining lung tissue. Similarly, inflammatory cytokines (IL-5 and IL-13) were also decreased in OVX-E2-OVA-treated animals in comparison to Female-INTACT-OVA mice in the BAL, but in the lung tissue IL-5, IL-13 and IL-33 were comparable in OVX-E2-OVA and F-INTACT OVA mice. ILC2 were sorted from the lungs and stimulated with exogenous IL-33. These ILC2 had reduced cytokine and chemokine expression when they were isolated from OVX-E2-OVA animals, indicating that steady-state estrogen suppresses IL-33-mediated activation of ILC2., Conclusions: Therapeutically targeting estrogen receptors may have a limiting effect on eosinophils, ILC2 and potentially other immune populations that may improve asthma symptoms in those females that experience perimenstrual worsening of asthma, with the caveat, that long-term use of estrogens or hormone receptor modulators may be detrimental to the lung microenvironment over time., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Livestock workers experience an increased burden of bioaerosol-induced respiratory disease including a high prevalence of rhinosinusitis. Dairy operations generate bioaerosols spanning the inhalable size fraction (0-100 μm) containing bacterial constituents such as endotoxin. Particles with an aerodynamic diameter between 10 and 100 μm are known to deposit in the nasopharyngeal region and likely affect the upper respiratory tract. We evaluated the effectiveness of a hypertonic saline nasal lavage in reducing inflammatory responses in dairy workers from a high-volume dairy operation. Inhalable personal breathing zone samples and pre-/post-shift nasal lavage samples from each participant over five consecutive days were collected. The treatment group (n = 5) received hypertonic saline while the control group (n = 5) received normotonic saline. Personal breathing zone samples were analyzed for particulate concentrations and endotoxin using gravimetric and enzymatic methods, respectively. Pro- and anti-inflammatory cytokines (i.e., IL-8, IL-10, and TNF-α) were measured from nasal lavage samples using a multiplex assay. Inhalable dust concentrations ranged from 0.15 to 1.9 mg/m 3 . Concentrations of both pro- and anti-inflammatory cytokines, specifically IL-6, IL-8, and IL-10, were significantly higher in the treatment group compared to the control group ( p  < 0.02, p  < 0.04, and p  < 0.01, respectively). Further analysis of IL-10 anti-inflammatory indicates a positive association between hypertonic saline administration and IL-10 production. This pilot study demonstrates that hypertonic saline nasal lavages were successful in upregulating anti-inflammatory cytokines to support larger interventional studies.

Objective: MUC5B and TOLLIP single nucleotide polymorphisms (SNPs) and cigarette smoking were associated with rheumatoid arthritis-interstitial lung disease (RA-ILD) in a predominantly Northern European population. We evaluated whether RA-ILD is associated with these genetic variants and HLA-DRB1 shared epitope (SE) alleles in a large RA cohort stratified by race and smoking history., Methods: HLA-DRB1 SE alleles and MUC5B rs35705950 and TOLLIP rs5743890 SNPs were genotyped in U.S. veterans with RA. ILD was validated through medical record review. Genetic associations with ILD were assessed in logistic regression models overall and in subgroups defined by race and smoking status, with additive interactions assessed by the relative excess risk of interaction (RERI)., Results: Of 2,556 participants (88% male, 77% White), 238 (9.3%) had ILD. The MUC5B variant was associated with ILD (OR 2.25 [95% CI 1.69, 3.02]), whereas TOLLIP and HLA-DRB1 SE were not. The MUC5B variant was less frequent among Black/African American participants (5.8% vs. 22.6%), though its association with RA-ILD was numerically stronger (OR 4.23 [1.65, 10.86]) compared to all other participants (OR 2.32 [1.70, 3.16]). Those with the MUC5B variant and a smoking history had numerically higher odds of ILD (OR 4.18 [2.53, 6.93]) than non-smokers (OR 2.41 [1.16, 5.04]). Additive interactions between MUC5B-race and MUC5B-smoking were not statistically significant., Conclusion: In this large RA cohort, the MUC5B promoter variant was associated with >2-fold higher odds of RA-ILD. While this variant is less common among Black/African American patients, its presence in this population carried >4-fold higher odds of RA-ILD., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Identify key features of IL-33 immunobiology important in allergic and nonallergic airway inflammatory diseases and potential therapeutic strategies to reduce disease burden., Data Sources: PubMed, clinicaltrials.gov., Study Selections: A systematic and focused literature search was conducted of PubMed from March 2021 to December 2021 using keywords to either PubMed or BioMed Explorer including IL-33/ST2, genetic polymorphisms, transcription, translation, post-translation modification, nuclear protein, allergy, asthma, and lung disease. Clinical trial information on IL-33 was extracted from clinicaltrials.gov in August 2021., Results: In total, 72 publications with relevance to IL-33 immunobiology and/or clinical lung disease were identified (allergic airway inflammation/allergic asthma n  = 26, non-allergic airway inflammation n  = 9, COPD n  = 8, lung fibrosis n  = 10). IL-33 levels were higher in serum, BALF and/or lungs across inflammatory lung diseases. Eight studies described viral infections and IL-33 and 4 studies related to COVID-19. Mechanistic studies ( n  = 39) including transcript variants and post-translational modifications related to the immunobiology of IL-33. Single nucleotide polymorphism in IL-33 or ST2 were described in 9 studies (asthma n  = 5, inflammatory bowel disease n  = 1, mycosis fungoides n  = 1, ankylosing spondylitis n  = 1, coronary artery disease n  = 1). Clinicaltrials.gov search yielded 84 studies of which 17 were related to therapeutic or biomarker relevance in lung disease., Conclusion: An integral role of IL-33 in the pathogenesis of allergic and nonallergic airway inflammatory disease is evident with several emerging clinical trials investigating therapeutic approaches. Current data support a critical role of IL-33 in damage signaling, repair and regeneration of lungs.

Purpose of Review: Adverse occupational and environmental exposures are common causes of respiratory disease and health consequences requiring medical care. Understanding how these various exposures affect patients and how to elicit an adequate history is critical for any clinician. Military personnel are often overlooked when discussing groups at risk for environmental exposure-associated airway disease. There are close to 20 million active duty and veterans in the USA, and nearly all clinicians will at some point care for a patient that has served in the military., Recent Findings: Exposures related to military work include burn pits, chemicals/toxins, sandstorms, and living conditions. Burn pits and military waste are increasingly recognized as potential hazards attributed to the ongoing conflicts in the Middle East. The link between these various military exposures and acute or chronic airway diseases remains difficult. Epidemiological studies are emerging to demonstrate correlations with chronic lung disease and prolonged burn pit exposure. This review provides an overview of potential occupational and environmental exposures that may affect current and/or former military service men and women., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: To determine whether RA and interstitial lung disease (ILD) severity measures are associated with survival in patients with RA-ILD., Methods: We studied US veterans with RA-ILD participating in a multicentre, prospective RA cohort study. RA disease activity (28-joint DAS [DAS28-ESR]) and functional status (multidimensional HAQ [MDHAQ]) were collected longitudinally while pulmonary function tests (forced vital capacity [FVC], diffusing capacity for carbon monoxide) were obtained from medical records. Vital status and cause of death were determined from the National Death Index and administrative data. Predictors of death were assessed using multivariable Cox regression models adjusting for age, sex, smoking status, ILD duration, comorbidity burden and medications., Results: We followed 227 RA-ILD participants (93% male and mean age of 69 years) over 1073 person-years. Median survival after RA-ILD diagnosis was 8.5 years. Respiratory diseases (28%) were the leading cause of death, with ILD accounting for 58% of respiratory deaths. Time-varying DAS28-ESR (adjusted hazard ratio [aHR] 1.21; 95% CI: 1.03, 1.41) and MDHAQ (aHR 1.85; 95% CI: 1.29, 2.65) were separately associated with mortality independent of FVC and other confounders. Modelled together, the presence of either uncontrolled disease activity (moderate/high DAS28-ESR) or FVC impairment (<80% predicted) was significantly associated with mortality risk. Those with a combination of moderate/high disease activity and FVC <80% predicted had the highest risk of death (aHR 4.43; 95% CI: 1.70, 11.55)., Conclusion: Both RA and ILD disease severity measures are independent predictors of survival in RA-ILD. These findings demonstrate the prognostic value of monitoring the systemic features of RA-ILD., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2022.)

Purpose: The objective of this article is to review recent literature on the implications of agricultural factors including pesticides, animal/livestock production facilities, agricultural dust, endotoxin, biomass/crop burning, and nutritional factors with respiratory health., Methods: PubMed, Embase, and CINAHL literature searches for the years 2016 to 2021 were conducted with librarian assistance., Results: Several studies suggest increased risk for asthma or wheeze with certain rural exposures, particularly for pesticides, livestock production facilities, agricultural dust, and biomass and crop burning., Conclusion: A complex network of environmental factors exists, which may have detrimental effects on the respiratory health of rural residents., Competing Interests: Funding and disclosures J.A. Poole has received funding from the Department of Defense (PR200793), the National Institute for Occupational Safety and Health (U54OH010162 and R01OH012045), and the Central States Center of Agricultural Safety and Health (CS-CASH). J.A. Poole has received research funding from AstraZeneca and clinical research funding from Takeda and GlaxoSmithKline., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rheumatoid arthritis (RA) occurs as the result of a complex interplay of environmental factors in a genetically susceptible individual. There is considerable evidence that the lungs may serve as an initial site of tolerance loss in the generation of RA-related autoimmunity, and several environmental inhalant exposures and lung diseases have been associated with RA risk. There is additional evidence that immune and microbial dysregulation of other mucosal sites, including the oral and gastrointestinal mucosa, may contribute to the development of RA. Epidemiologic evidence linking mucosal exposures to various environmental insults as risk determinants in RA will be reviewed., (Published by Elsevier Inc.)

Although lung diseases typically result from long-term exposures, even a robust, one-time exposure can result in long-lasting consequences. Endotoxin is a ubiquitous environmental/occupational inflammatory agent often used to model airway inflammation. Using a murine model, the return to lung homeostasis following high dose inhalant lipopolysaccharide (LPS, 10-100 μg) exposure were delineated over 2 weeks. LPS-induced rapid weight loss, release of proinflammatory mediators, and inflammatory cell influx with prolonged persistence of activated macrophages CD11c + CD11b + and recruited/transitioning CD11c int CD11b + monocyte-macrophages out to 2 weeks. Next, lung-delivered recombinant (r) interleukin (IL)-10 was intratracheally administered for 3 doses initiated 5 h following LPS (10 μg) exposure for 2 days. IL-10 therapy reduced LPS-induced weight loss and increased blood glucose levels. Whereas there was no difference in LPS-induced bronchoalveolar lavage airway fluid cellular influx, total lung cell infiltrates were reduced (37%) with rIL-10 treatment. Post-LPS exposure treatment with rIL-10 strikingly reduced lavage fluid and lung homogenate levels of tumor necrosis factor-α (88% and 93% reduction, respectively), IL-6 (98% and 94% reduction), CXCL1 (66% and 75% reduction), and CXCL2 (47% and 67% reduction). LPS-induced recruited monocyte-macrophages (CD11c int CD11b + ) were reduced (68%) with rIL-10. Correspondingly, LPS-induced lung tissue CCR2 + inflammatory monocyte-macrophage were reduced with rIL-10. There were also reductions in LPS-induced lung neutrophils, lymphocyte subpopulations, collagen content, and vimentin expression. These findings support the importance of studying resolution processes for the development of treatment after unintended environmental/occupational biohazard exposures. Short-term, lung-delivered rIL-10 favorably hastened inflammatory recovery processes following acute, high dose inhalant LPS exposure., (© 2022. The Author(s).)

Background: The club cell secretory protein (CC16) has anti-inflammatory and antioxidant effects, and low CC16 serum levels have been associated with both risk and progression of COPD, yet the interaction between smoking and CC16 on lung function outcomes remains unknown., Methods: Utilizing cross-sectional data on United States veterans, CC16 serum concentrations were measured by ELISA and log transformed for analyses. Spirometry was conducted and COPD status was defined by post-bronchodilator FEV 1 /FVC ratio < 0.7. Smoking measures were self-reported on questionnaire. Multivariable logistic and linear regression were employed to examine associations between CC16 levels and COPD, and lung function with adjustment for covariates. Unadjusted Pearson correlations described relationships between CC16 level and lung function measures, pack-years smoked, and years since smoking cessation., Results: The study population (N = 351) was mostly male, white, with an average age over 60 years. An interaction between CC16 and smoking status on FEV 1 /FVC ratio was demonstrated among subjects with COPD (N = 245, p = 0.01). There was a positive correlation among former smokers and negative correlation among current or never smokers with COPD. Among former smokers with COPD, CC16 levels were also positively correlated with years since smoking cessation, and inversely related with pack-years smoked. Increasing CC16 levels were associated with lower odds of COPD (OR adj  = 0.36, 95% CI 0.22-0.57, P adj  < 0.0001)., Conclusions: Smoking status is an important effect modifier of CC16 relationships with lung function. Increasing serum CC16 corresponded to increases in FEV 1 /FVC ratio in former smokers with COPD versus opposite relationships in current or never smokers. Additional longitudinal studies may be warranted to assess relationship of CC16 with smoking cessation on lung function among subjects with COPD., (© 2022. The Author(s).)

Exposure to air pollutants is known to exacerbate asthma, with prior studies focused on associations between single pollutant exposure and asthma exacerbations. As air pollutants often exist as a complex mixture, there is a gap in understanding the association between complex air pollutant mixtures and asthma exacerbations. We evaluated the association between the air pollutant mixture (52 pollutants) and pediatric asthma exacerbations., Method: This study focused on children (age ≤ 19 years) who lived in Douglas County, Nebraska, during 2016-2019. A seasonal-scale joint association between the outdoor air pollutant mixture adjusting for potential confounders (temperature, precipitation, wind speed, and wind direction) in relation to pediatric asthma exacerbation-related emergency department (ED) visits was evaluated using the generalized weighted quantile sum (qWQS) regression with repeated holdout validation., Results: We observed associations between air pollutant mixture and pediatric asthma exacerbations during spring (lagged by 5 days), summer (lag 0-5 days), and fall (lag 1-3 days) seasons. The estimate of the joint outdoor air pollutant mixture effect was higher during the summer season (adjusted-β WQS = 1.11, 95% confidence interval [CI]: 0.66, 1.55), followed by spring (adjusted-β WQS = 0.40, 95% CI: 0.16, 0.62) and fall (adjusted-β WQS = 0.20, 95% CI: 0.06, 0.33) seasons. Among the air pollutants, PM 2.5 , pollen, and mold contributed higher weight to the air pollutant mixture., Conclusion: There were associations between outdoor air pollutant mixture and pediatric asthma exacerbations during the spring, summer, and fall seasons. Among the 52 outdoor air pollutant metrics investigated, PM 2.5 , pollen (sycamore, grass, cedar), and mold ( Helminthosporium , Peronospora , and Erysiphe ) contributed the highest weight to the air pollutant mixture., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Cannabis is the most widely used recreational drug in the world. Cannabis sativa and Cannabis indica have been selectively bred to develop their psychoactive properties. The increasing use in many countries has been accelerated by the COVID-19 pandemic. Cannabis can provoke both type 1 and type 4 allergic reactions. Officially recognized allergens include a pathogenesis-related class 10 allergen, profilin, and a nonspecific lipid transfer protein. Other allergens may also be relevant, and recognition of allergens may vary between countries and continents. Cannabis also has the potential to provoke allergic cross-reactions to plant foods. Since cannabis is an illegal substance in many countries, research has been hampered, leading to challenges in diagnosis since no commercial extracts are available for testing. Even in countries such as Canada, where cannabis is legalized, diagnosis may rely solely on the purchase of cannabis for prick-to-prick skin tests. Management consists of avoidance, with legal issues hindering the development of other treatments such as immunotherapy. Education of healthcare professionals is similarly lacking. This review aimed to summarize the current status of cannabis allergy and proposes recommendations for the future management of this global issue., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Immunogenetic as well as environmental and occupational exposures have been linked to the development of rheumatoid arthritis (RA), RA-associated lung disease, and other primary lung disorders. Importantly, various inhalants can trigger post-translational protein modifications, resulting in lung autoantigen expression capable of stimulating pro-inflammatory and/or pro-fibrotic immune responses. To further elucidate gene-environment interactions contributing to pathologic lung inflammation, we exploited an established model of organic dust extract (ODE) exposure with and without collagen-induced arthritis (CIA) in C57BL/6 wild type (WT) versus HLA-DR4 transgenic mice. ODE-induced airway infiltration driven by neutrophils was significantly increased in DR4 versus WT mice, with corresponding increases in bronchoalveolar lavage fluid (BALF) levels of TNF-⍺, IL-6, and IL-33. Lung histopathology demonstrated increased number of ectopic lymphoid aggregates comprised of T and B cells following ODE exposure in DR4 mice. ODE also induced citrullination, malondialdehyde acetaldehyde (MAA) modification, and vimentin expression that co-localized with MAA and was enhanced in DR4 mice. Serum and BALF anti-MAA antibodies were strikingly increased in ODE-treated DR4 mice. Coupling ODE exposure with Type II collagen immunization (CIA) resulted in similarly augmented pro-inflammatory lung profiles in DR4 mice (relative to WT mice) that was accompanied by a profound increase in infiltrating lung CD4 + and CD8 + T cells as well as CD19 + CD11b + autoimmune B cells. Neither modeling strategy induced significant arthritis. These findings support a model in which environmental insults trigger enhanced post-translational protein modification and lung inflammation sharing immunopathological features with RA-associated lung disease in the selected immunogenetic background of HLA-DR4 mice., (© 2022. The Author(s).)

Agriculture workers report various respiratory symptoms owing to occupational exposure to organic dust (OD) and various gases. Previously, we demonstrated that pre-exposure to hydrogen sulfide (H 2 S) alters the host response to OD and induces oxidative stress. Nrf2 is a master-regulator of host antioxidant response and exposures to toxicants is known to reduce Nrf2 activity. The OD exposure-induced lung inflammation is known to increase susceptibility to a secondary microbial infection. We tested the hypothesis that repeated exposure to OD or H 2 S leads to loss of Nrf2, loss of epithelial cell integrity and that activation of Nrf2 rescues this epithelial barrier dysfunction. Primary normal human bronchial epithelial (NHBE) cells or mouse precision cut-lung slices (PCLS) were treated with media, swine confinement facility organic dust extract (ODE) or H 2 S or ODE+H 2 S for one or five days. Cells were also pretreated with vehicle control (DMSO) or RTA-408, a Nrf2 activator. Acute exposure to H 2 S and ODE+H 2 S altered the cell morphology, decreased the viability as per the MTT assay, and reduced the Nrf2 expression as well as increased the keap1 levels in NHBE cells. Repeated exposure to ODE or H 2 S or ODE+H 2 S induced oxidative stress and cytokine production, decreased tight junction protein occludin and cytoskeletal protein ezrin expression, disrupted epithelial integrity and resulted in increased Klebsiella pneumoniae invasion. RTA-408 (pharmacological activator of Nrf2) activated Nrf2 by decreasing keap1 levels and reduced ODE+H 2 S-induced changes including reversing loss of barrier integrity, inflammatory cytokine production and microbial invasion in PCLS but not in NHBE cell model. We conclude that Nrf2 activation has a partial protective function against ODE and H 2 S., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shrestha, Massey, Bhat, Jelesijević, Sahin, Zhang, Bailey, Poole and Charavaryamath.)