Assessing the impact of air pollutants on clinical visits for childhood allergic respiratory disease induced by house dust mite in Shanghai, China.

BACKGROUND: The prevalence of allergic respiratory disease (ARD) is increasing worldwide during the last few decades, causing a great disease burden especially for children. Air pollution has been increasingly considered as a potential contributor to this trend, but its role in ARD induced by house dust mite (HDM-ARD) remains unclear, especially in time-series study. METHODS: A positive reporting of respiratory allergy to named allergens was included by serum specific IgE testing. A time series Quasi-Poisson regression with distributed lag non-linear model, combined with generalized linear model was used to examine the effects of air pollutants on ARD, HDM-ARD and ARD induced by non-house dust mite (NHDM-ARD). RESULTS: A total of 16,249 cases of ARD, including 8,719 HDM-ARD and 8,070 NHDM-ARD from 1 Jan 2013 to 31 Dec 2017 were involved in this study. Air pollutants were significantly associated with clinical visits for childhood ARD and HDM-ARD. Exposure to higher O3 and interquartile range (IQR) increment in O3 (40.6 µg/m3) increased the risks of clinical visits for childhood HDM-ARD (RRlag0-5 for the 95th percentile of O3: 1.26, 95% confidence interval (CI): 1.03, 1.55; RRlag0-5 for IQR increment (40.6 µg/m3): 1.09, 95% CI: 1.01, 1.17) and ARD (RRlag0-5 for the 95th percentile of O3: 1.19, 95% CI: 1.03, 1.38; RRlag0-5 for IQR increment (40.6 µg/m3): 1.06, 95% CI: 1.01, 1.12). In addition, higher O3 was associated with increased RR of boys with ARD (RRlag0-5 for the 95th percentile: 1.26, 95% CI: 1.05, 1.51; RRlag0-5 for IQR increment (40.6 µg/m3): 1.09, 95% CI: 1.02, 1.16) and HDM-ARD (RRlag0-5 for the 95th percentile: 1.36, 95% CI: 1.06, 1.75; RRlag0-5 for IQR increment (40.6 µg/m3): 1.11, 95% CI: 1.02, 1.22), but not in girls. CONCLUSIONS: Exposure to O3 appeared to be a trigger of clinical visits for childhood ARD, especially for HDM-ARD and boys. These findings provide novel evidence on the impact of air pollution on HDM-ARD, which may have significant implications for designing effective intervention programs to control and prevent childhood ARD, especially HDM-ARD, in China and other similar developing countries.

Home Dust Allergen Exposure Is Associated with Outcomes among Sensitized Individuals with Chronic Obstructive Pulmonary Disease.

Rationale: Environmental exposures have been associated with adverse outcomes in chronic obstructive pulmonary disease (COPD). Approximately one-third of individuals with COPD have allergic sensitization, but it is unknown whether exposure to allergens in the home is associated with outcomes. Objectives: To determine the prevalence and associations of allergen sensitization with exposure to common indoor allergens with symptoms and exacerbation risk in COPD. Methods: Allergen sensitization to five common indoor allergens was assessed in former smokers with COPD. Home settled dust was assessed for presence of corresponding allergens. Sensitization and exposure status was determined and associations evaluated in adjusted models with longitudinal outcomes including symptoms, lung function, and exacerbations. Interactions were assessed between sensitization/exposure status and lung function. Measurements and Main Results: One hundred eighty-three individuals studied were on average 67.3 years of age (SD, 8.22) with average FEV1 of 53.2% (SD, 17.6%). Seventy-seven percent of participants were exposed to at least one tested allergen, and 17% had sensitization with corresponding allergen exposure. After adjustment, sensitization with exposure was associated with lower lung function (ß, -8.29; 95% confidence interval [CI], -14.80 to -1.77), higher St. George's Respiratory Questionnaire Total Score (ß, 6.71; 95% CI, 0.17 to 13.25), and higher exacerbation risk (odds ratio, 2.31; 95% CI, 1.11 to 4.79). Associations appeared to be more pronounced among individuals with lower lung function. Conclusions: Allergen exposures are common in COPD and associated with adverse outcomes among those with concomitant allergen sensitization. This study establishes allergens as an important home exposure that potentially could be addressed with comprehensive home environmental modification strategies to improve COPD outcomes.

Airway IL-1ß associates with IL-5 production following dust mite allergen inhalation in humans.

BACKGROUND: Preclinical studies implicate interleukin (IL)-1ß as a key mediator of asthma and have shown the efficacy of IL-1 antagonism for treatment of allergic airway inflammation; human studies in this area are lacking. OBJECTIVES: Our aim was to study the relationship of airway IL-1ß to features of acute allergen-induced asthma exacerbation in humans. METHODS: Dust mite-allergic adults with mild asthma underwent inhalation challenge with Dermatophagoides farinae. Fractional exhaled nitric oxide (FeNO), induced sputum and peripheral blood samples were obtained pre- and 24 h post-challenge. Spirometry was performed before and throughout the challenge at 10-min intervals, and allergen responsiveness was defined by a 20% fall in Forced Expiratory Volume in 1 s (FEV1). Sputum samples were analyzed for inflammatory cells, cytokines and chemokines. Multiple linear regression was employed to test the association between sputum IL-1ß concentration and biomarkers of T helper type 2 (T2)-dominant inflammation. RESULTS: Fourteen volunteers underwent inhaled allergen challenge. Allergen responsive volunteers showed a greater positive change in IL-1ß in sputum following allergen challenge compared to non-responders. Higher pre-challenge sputum IL-1ß was associated with greater increase in sputum IL-5 (p = 0.004), sputum eosinophils (p = 0.001) and blood IL-5 (p = 0.003) following allergen challenge. Allergen-induced sputum IL-1ß production was significantly associated with sputum and blood IL-5 (p < 0.001 and p = 0.007, respectively), sputum IL-4 (p = 0.001), IL-13 (p = 0.026), eosinophils (p = 0.008) and FeNO (p = 0.03). CONCLUSIONS: The positive association between production of IL-1ß and biomarkers of T2 inflammation, particularly IL-5, in humans is consistent with work in animal models that demonstrates a link between IL-1ß and the pathophysiology of allergic asthma. The role of IL-1ß in human asthma warrants further study.

Inflammatory and immunological profile in COPD secondary to organic dust exposure.

Inflammatory response in patients with COPD secondary to organic dust exposure (OD-COPD) is poorly understood. We therefore aimed to characterize inflammatory and immune profile from peripheral blood mononuclear cells (PBMC) in a group of patients with mild-to-moderate COPD secondary to organic dust exposure (OD-COPD), tobacco smoking (T-COPD), or both. We compared T, B and NK cells distribution and inflammatory (TNF-α, Il-1ß, IL-6), type 1 (IFN-γ), type 2 (IL-4, IL-13) and type 3 (IL-17) immunity related cytokines at baseline, and after stimulation with LPS, flagellin and CD3/CD28 beads in all COPD groups. OD-COPD displayed significantly lower NK cells and CD8+ T cells compared with controls. After flagellin stimulation, T-COPD had significantly lower IL-13 levels than OD-COPD and controls (p < 0.05) whereas IFN-γ tended to be lower in OD-COPD. All COPD groups displayed higher IL-1ß and IL-17 than controls after CD3/CD28 stimulation. Inflammatory responses in OD-COPD were different from T-COPD. OD-COPD displayed higher levels of type 2 immunity related cytokines.

Prevalence of allergen-specific IgE in southern China: a multicenter research.

Identifying allergen distribution is meaningful and significant for effective diagnosis and treatment of allergic diseases. This study compared the allergen sensitivity in four southern China cities. We enrolled 55,432 participants (27,408 male, 28,024 female) between 2007 and 2019. The allergen-specific IgE levels were compared by the χ2 test. The five prevalent sensitivities were for mite mix (10,985, 19.82%), cockroach (4,860, 8.77%), crab (4,450, 8.03%), fish mix (3,874, 6.99%), and house dust (3,486, 6.29%). Almost all allergen sensitivities decreased with age, particularly from infant to middle aged participants (p < 0.05). An exception was Shenzhen, where food allergen positive rates remained constant in all age groups studied. The proportion of male sensitive to at least one food allergen (OR 1.130; 95% CI 1.088-1.174, p < 0.0025) or aeroallergen (OR, 1.117; 95% CI, 1.078-1.158, p < 0.0025) was higher than female in all four cities. Except for dog dander and tree mix, all aeroallergens differed significantly between seasons (p < 0.05). Liuzhou had the highest rates of food allergen- and aeroallergen-positive participants. The allergen-specific IgE distribution differed among the studied cities, with significant seasonal differences. Young age, male sex, and aeroallergens were risk factors for allergic disease.

Effects of elevated CO2 levels on lung immune response to organic dust and lipopolysaccharide.

Workplaces with elevated organic dust levels such as animal feed barns also commonly have elevated levels of gasses, such as CO2. Workers exposed to such complex environments often experience respiratory effects that may be due to a combination of respirable factors. We examined the effects of CO2 on lung innate immune responses in mice co-exposed to the inflammatory agents lipopolysaccharide (LPS) and organic dust. We evaluated CO2 levels at the building recommended limit (1000 ppm) as well as the exposure limit (5000 ppm). Mice were nasally instilled with dust extracts or LPS and immediately put into chambers with a constant flow of room air (avg. 430 ppm CO2), 1000 ppm, or 5000 ppm CO2 enriched air. Results reveal that organic dust exposures tended to show decreased inflammatory responses with 1000 ppm CO2 and increased responses at 5000 ppm CO2. Conversely, LPS with addition of CO2 as low as 1000 ppm tended to inhibit several inflammatory markers. In most cases saline treated animals showed few changes with CO2 exposure, though some changes in mRNA levels were present. This shows that CO2 as low as 1000 ppm CO2 was capable of altering innate immune responses to both LPS and organic dust extracts, but each response was altered in a different fashion.

Mine-site derived particulate matter exposure exacerbates neurological and pulmonary inflammatory outcomes in an autoimmune mouse model.

The Southwestern United States has a legacy of industrial mining due to the presence of rich mineral ore deposits. The relationship between environmental inhaled particulate matter (PM) exposures and neurological outcomes within an autoimmune context is understudied. The aim of this study was to compare two regionally-relevant dusts from high-priority abandoned mine-sites, Claim 28 PM, from Blue Gap Tachee, AZ and St. Anthony mine PM, from the Pueblo of Laguna, NM and to expose autoimmune-prone mice (NZBWF1/J). Mice were randomly assigned to one of three groups (n = 8/group): DM (dispersion media, control), Claim 28 PM, or St. Anthony PM, subjected to oropharyngeal aspiration of (100 µg/50 µl), once per week for a total of 4 consecutive doses. A battery of immunological and neurological endpoints was assessed at 24 weeks of age including: bronchoalveolar lavage cell counts, lung gene expression, brain immunohistochemistry, behavioral tasks and serum autoimmune biomarkers. Bronchoalveolar lavage results demonstrated a significant increase in number of polymorphonuclear neutrophils following Claim 28 and St. Anthony mine PM aspiration. Lung mRNA expression showed significant upregulation in CCL-2 and IL-1ß following St. Anthony mine PM aspiration. In addition, neuroinflammation was present in both Claim 28 and St. Anthony mine-site derived PM exposure groups. Behavioral tasks resulted in significant deficits as determined by Y-maze new arm frequency following Claim 28 aspiration. Neutrophil elastase was significantly upregulated in the St. Anthony mine exposure group. Interestingly, there were no significant changes in serum autoantigens suggesting systemic inflammatory effects may be mediated through other molecular mechanisms following low-dose PM exposures.

House dust mite sensitization drives cross-reactive immune responses to homologous helminth proteins.

The establishment of type 2 responses driven by allergic sensitization prior to exposure to helminth parasites has demonstrated how tissue-specific responses can protect against migrating larval stages, but, as a consequence, allow for immune-mediated, parasite/allergy-associated morbidity. In this way, whether helminth cross-reacting allergen-specific antibodies are produced and play a role during the helminth infection, or exacerbate the allergic outcome awaits elucidation. Thus, the main objective of the study was to investigate whether house dust mite (HDM) sensitization triggers allergen-specific antibodies that interact with Ascaris antigens and mediate antibody-dependent deleterious effects on these parasites as well as, to assess the capacity of cross-reactive helminth proteins to trigger allergic inflammation in house dust mite presensitized mice. Here, we show that the sensitization with HDM-extract drives marked IgE and IgG1 antibody responses that cross-react with Ascaris larval antigens. Proteomic analysis of Ascaris larval antigens recognized by these HDM-specific antibodies identified Ascaris tropomyosin and enolase as the 2 major HDM homologues based on high sequence and structural similarity. Moreover, the helminth tropomyosin could drive Type-2 associated pulmonary inflammation similar to HDM following HDM tropomyosin sensitization. The HDM-triggered IgE cross-reactive antibodies were found to be functional as they mediated immediate hypersensitivity responses in skin testing. Finally, we demonstrated that HDM sensitization in either B cells or FcγRIII alpha-chain deficient mice indicated that the allergen driven cell-mediated larval killing is not antibody-dependent. Taken together, our data suggest that aeroallergen sensitization drives helminth reactive antibodies through molecular and structural similarity between HDM and Ascaris antigens suggesting that cross-reactive immune responses help drive allergic inflammation.

High-throughput analysis of lung immune cells in a combined murine model of agriculture dust-triggered airway inflammation with rheumatoid arthritis.

Rheumatoid arthritis (RA)-associated lung disease is a leading cause of mortality in RA, yet the mechanisms linking lung disease and RA remain unknown. Using an established murine model of RA-associated lung disease combining collagen-induced arthritis (CIA) with organic dust extract (ODE)-induced airway inflammation, differences among lung immune cell populations were analyzed by single cell RNA-sequencing. Additionally, four lung myeloid-derived immune cell populations including macrophages, monocytes/macrophages, monocytes, and neutrophils were isolated by fluorescence cell sorting and gene expression was determined by NanoString analysis. Unsupervised clustering revealed 14 discrete clusters among Sham, CIA, ODE, and CIA+ODE treatment groups: 3 neutrophils (inflammatory, resident/transitional, autoreactive/suppressor), 5 macrophages (airspace, differentiating/recruited, recruited, resident/interstitial, and proliferative airspace), 2 T-cells (differentiating and effector), and a single cluster each of inflammatory monocytes, dendritic cells, B-cells and natural killer cells. Inflammatory monocytes, autoreactive/suppressor neutrophils, and recruited/differentiating macrophages were predominant with arthritis induction (CIA and CIA+ODE). By specific lung cell isolation, several interferon-related and autoimmune genes were disproportionately expressed among CIA and CIA+ODE (e.g. Oasl1, Oas2, Ifit3, Gbp2, Ifi44, and Zbp1), corresponding to RA and RA-associated lung disease. Monocytic myeloid-derived suppressor cells were reduced, while complement genes (e.g. C1s1 and Cfb) were uniquely increased in CIA+ODE mice across cell populations. Recruited and inflammatory macrophages/monocytes and neutrophils expressing interferon-, autoimmune-, and complement-related genes might contribute towards pro-fibrotic inflammatory lung responses following airborne biohazard exposures in setting of autoimmune arthritis and could be predictive and/or targeted to reduce disease burden.

Hygiene hypothesis: association between hygiene and asthma among preschool children in Lebanon

OBJECTIVES: To validate a scale to assess the hygiene hypothesis and the association between hygiene and asthma among Lebanese preschool children aged 3-5 years. METHODS: This cross-sectional study, conducted between November 2018 and March 2019, enrolled 515 preschool children. Asthma and potential risk factors, including hygiene, were assessed using a standardized questionnaire. A specific hygiene hypothesis scale has been gen­erated and validated for this purpose. RESULTS: The hygiene hypothesis scale items converged over a solution of nine factors that had an Eigenvalue over 1, explaining a total of 65.86% of the variance. An acceptable Cronbach's alpha value was recorded for the hygiene hypothesis scale (0.696). Variables correlated with higher odds of asthma were male gender (ORa = 0.41 for females), living near a prairie sprayed with pesticides (ORa = 3.09), having a heating system in the bedroom compared to the sitting room (ORa = 9.97), attending kindergarten (ORa = 2.80), having a mother who smokes water­pipe compared to not smoking (ORa = 3.34), having a mother with a history of asthma (ORa = 5.50), and having respiratory infections (ORa = 14.72). However, the hygiene hypothesis score was not associated with higher odds of asthma (p = 0.881). CONCLUSIONS: The current results suggested that neither home cleaning nor personal cleanliness was correlated with asthma in preschool children. Larger prospective studies that measure the intensity and duration of exposure to each toxicant are suggested to better assess the hygiene hypothesis items and their association with asthma

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IgE-binding residues analysis of the house dust mite allergen Der p 23.

House dust mites (HDMs) are one of the major causes of allergies in the world. The group 23 allergen, Der p 23, from Dermatophagoides pteronyssinus, is a major allergen amongst HDM-sensitized individuals. This study aims to determine the specific immunoglobulin E (sIgE) binding frequency and IgE-binding residues of recombinant Der p 23 (rDer p 23) allergen amongst a cohort of consecutive atopic individuals in a tropical region. We performed site-directed mutagenesis and carried out immuno-dot blot assays using 65 atopic sera. The immuno-dot blot assays results indicated that the two residues K44 and E46 which are located at the N-terminal region are the major IgE-binding residues. The rDerp-23 sIgE titers are strongly correlated to the number of IgE-binding residues for rDer p 23 (P < 0.001). Atopic individuals who were only sensitized to HDM have a significantly higher number of IgE-binding residues than the individuals who were polysensitized to HDM and other crude allergens (P < 0.05). Individuals with allergic multimorbidity and moderate-to-severe allergic rhinitis also have a higher number of IgE-binding residues compared to those with single allergic disease and mild allergic rhinitis. The results prompt us to hypothesize that the individuals who have a higher number of IgE-binding residues may face a bigger challenge to be treated through immunotherapy due to the complexity in designing an effective hypoallergen with a high number of IgE-binding residues. We propose that the development of a refined molecular diagnostic assay, which includes alanine substitution of surface-exposed residues could be a more precise diagnostic strategy to identify all the IgE-binding residues of a major allergen for an atopic individual and the development could be another new dimension in allergy diagnosis and allergen immunotherapy treatment.

Barrier Housing and Gender Effects on Allergic Airway Disease in a Murine House Dust Mite Model.

Allergic airway disease models use laboratory mice housed in highly controlled and hygienic environments, which provide a barrier between the mice and a predetermined list of specific pathogens excluded from the facility. In this study, we hypothesized that differences in facility barrier level and, consequently, the hygienic quality of the environment that mice inhabit impact the severity of pulmonary inflammation and lung function. Allergen-naive animals housed in the cleaner, high barrier (HB) specific pathogen-free facility had increased levels of inflammatory cytokines and higher infiltration of immune cells in the lung tissue but not in the bronchoalveolar lavage compared with mice housed in the less hygienic, low barrier specific pathogen-free facility. In both genders, house dust mite-induced airway disease was more severe in the HB than the low barrier facility. Within each barrier facility, female mice developed the most severe inflammation. However, allergen-naive male mice had worse lung function, regardless of the housing environment, and in the HB, the lung function in female mice was higher in the house dust mite model. Severe disease in the HB was associated with reduced lung microbiome diversity. The lung microbiome was altered across housing barriers, gender, and allergen-exposed groups. Thus, the housing barrier level impacts microbial-driven disease and gender phenotypes in allergic asthma. The housing of laboratory mice in more clean HB facilities aggravates lung immunity and causes a more severe allergic lung disease.

House dust microbiota in relation to adult asthma and atopy in a US farming population.

BACKGROUND: Bacterial exposure from house dust has been associated with asthma and atopy in children but whether these relationships are present in adults remains unclear. OBJECTIVE: We sought to examine associations of house dust microbiota with adult asthma, atopy, and hay fever. METHODS: Vacuumed bedroom dust samples from the homes of 879 participants (average age, 62 years) in the Agricultural Lung Health Study, a case-control study of asthma nested within a farming cohort, were subjected to 16S rRNA amplicon sequencing to characterize bacterial communities. We defined current asthma and hay fever using questionnaires and current atopy by blood specific IgE level > 0.70 IU/mL to 1 or more of 10 common allergens. We used linear regression to examine whether overall within-sample bacterial diversity differed by outcome, microbiome regression-based kernel association test to evaluate whether between-sample bacterial community compositions differed by outcome, and analysis of composition of microbiomes to identify differentially abundant bacterial taxa. RESULTS: Overall diversity of bacterial communities in house dust was similar by asthma status but was lower (P < .05) with atopy or hay fever. Many individual bacterial taxa were differentially abundant (false-discovery rate, <0.05) by asthma, atopy, or hay fever. Several taxa from Cyanobacteria, Bacteroidetes, and Fusobacteria were more abundant with asthma, atopy, or hay fever. In contrast, several taxa from Firmicutes were more abundant in homes of individuals with adequately controlled asthma (vs inadequately controlled asthma), individuals without atopy, or individuals without hay fever. CONCLUSIONS: Microbial composition of house dust may influence allergic outcomes in adults.

Exposure to additives or multigrain flour is associated with high risk of work-related allergic symptoms among bakers.

OBJECTIVES: Wheat flour exposure in bakers can elicit respiratory and skin symptoms. Scarce data are available on the prevalence of such conditions in bakers. We investigated the prevalence of work-related rhinitis, asthma-like symptoms and dermatitis in bakers according to job task and type of allergens involved. METHODS: Of the 229 traditional bakeries in Verona area who were invited to participate in a cross-sectional survey, 211 (92%) accepted; 727 employees in these bakeries answered a modified version of a questionnaire on job tasks; allergen exposure within the bakery; and work-related nasal, asthma-like and skin symptoms during 2010-2014. Determinants of work-related nasal, asthma-like or skin disorders were separately evaluated using different logistic models. RESULTS: The prevalence of work-related nasal and asthma-like symptoms was, respectively, 15.1% and 4.2% in bakery shop assistants, increasing to 25.7% and 9.5% in bakers using only wheat flour, and further to 31.8% and 13.6% in bakers using flour and additives, and then to 34.1% and 18.2% in bakers using flour with additives and multigrain (p<0.001). The risk of work-related asthma-like symptoms was more than doubled in bakers using additives without or with multigrain than in shop assistants (OR 2.3, 95% CI 1.0 to 5.5 and OR 3.4, 95% CI 1.1 to 10.8, respectively). Making bread with additives alone or with multigrain significantly increased the risk of work-related nasal symptoms in shop assistants, while the risk of skin symptoms was not significantly affected. CONCLUSIONS: Bakers using additives alone or with multigrain are at a high risk of experiencing nasal and asthma-like symptoms.

iTRAQ­based proteomic analysis reveals potential regulatory networks in dust mite­related asthma treated with subcutaneous allergen immunotherapy.

Asthma is one of the most common childhood chronic diseases worldwide. Subcutaneous immunotherapy (SCIT) is commonly used in the treatment of house dust mite (HDM)­related asthma in children. However, the therapeutic mechanism of SCIT in asthma remains unclear. The present study aimed to investigate the molecular biomarkers associated with HDM­related asthma in asthmatic children prior and subsequent to SCIT treatment compared with those in healthy children via proteomic analysis. The study included a control group (30 healthy children), ­Treatment group (30 children with HDM­related allergic asthma) and +Treatment group (30 children with HDM­related allergic asthma treated with SCIT). An isobaric labeling with relative and absolute quantification­based method was used to analyze serum proteome changes to detect differentially expressed proteins, while functional enrichment and protein­protein interaction network analysis were used to select candidate biomarkers. A total of 72 differentially expressed proteins were detected in the ­Treatment, +Treatment and control groups. A total of 33 and 57 differentially expressed proteins were observed in the ­Treatment vs. control and +Treatment vs. control groups, respectively. Through bioinformatics analysis, 5 candidate proteins [keratin 1 (KRT1), apolipoprotein B (APOB), fibronectin 1, antithrombin III (SERPINC1) and α­1­antitrypsin (SERPINA1)] were selected for validation by western blotting; among them, 4 proteins (KRT1, APOB, SERPINC1 and SERPINA1) showed robust reproducibility in asthma and control samples. This study illustrated the changes in proteome regulation following SCIT treatment for asthma. The 4 identified proteins may serve as potential biomarkers prior and subsequent to SCIT treatment, and help elucidate the molecular regulation mechanisms of SCIT to treat HDM­related asthma.

In vivo immune activation of splenocytes following exposure to tar from Asian sand dust.

Air pollution, especially that initiated by particulate matter (PM), has been implicated as a risk factor for several inflammatory diseases. Previously, it was reported that PM enhances immune responses. PM includes the tar fraction that contains polycyclic aromatic hydrocarbons (PAHs), which produce adverse health effects in exposed individuals. However, the influence of the tar fraction (as a component of PM) on splenocytes is not fully understood. The aim of this study was to determine the effects of the tar fraction extracted from PM collected from the atmosphere in Fukuoka, Japan, on mouse splenocytes. ICR mice were administered tar (1 or 5 µg/mouse) intratracheally 4 times at 2-week intervals, and splenocytes from the tar-treated mice were extracted and examined. The parameters determined were proliferation, cytokine concentrations and transcription factors activation. Following tar treatment, splenocyte proliferation increased relative to controls. Concanavalin A (ConA)-induced interleukin (IL)-2 formation and ConA- or lipopolysaccharide (LPS)-induced interferon-γ production were elevated in splenocytes from tar-exposed mice. However, the production of tumor necrosis factor-α and IL-6 induced by LPS was not markedly changed following tar treatment. Further, nuclear factor of activated T cells, but not nuclear factor-κB, was enhanced in splenocytes of tar-exposed mice. Data indicate that tar-activated splenocytes and PM-bound PAHs might contribute to T cell activation in the spleen.

Organic dust-induced lung injury and repair: Bi-directional regulation by TNFα and IL-10.

Exposure to organic dust increases chronic airway inflammatory disorders. Effective treatment strategies are lacking. It has been reported that hog barn dust extracts (HDE) induce TNFα through protein kinase C (PKC) activation and that lung inflammation is enhanced in scavenger receptor A (SRA/CD204) knockout (KO) mice following HDE. Because interleukin (IL)-10 production can limit excessive inflammation, it was hypothesized here that HDE-induced IL-10 would require CD204 to effect inflammatory responses. C57BL/6 wild-type (WT), SRA KO, and IL-10 KO mice were intranasally challenged daily for 8 days with HDE and subsequently rested for 3 days with/without recombinant IL-10 (rIL-10) treatment. Primary peritoneal macrophages (PM) and murine alveolar macrophages (MH-S cells) were treated in vitro with HDE, SRA ligand (fucoidan), rIL-10, and/or PKC isoform inhibitors. HDE induced in vivo lung IL-10 in WT, but not SRA KO mice, and similar trends were demonstrated in isolated PM from same treated mice. Lung lymphocyte aggregates and neutrophils were elevated in in vivo HDE-treated SRA and IL-10 KO mice after a 3-d recovery, and treatment during recovery with rIL-10 abrogated these responses. In vitro rIL-10 treatment reduced HDE-stimulated TNFα release in MH-S and WT PM. In SRA KO macrophages, there was reduced IL-10 and PKC zeta (ζ) activity and increased TNFα following in vitro HDE stimulation. Similarly, blocking SRA (24 hr fucoidan pre-treatment) resulted in enhanced HDE-stimulated macrophage TNFα and decreased IL-10 and PKCζ activation. PKCζ inhibitors blocked HDE-stimulated IL-10, but not TNFα. Collectively, HDE stimulates IL-10 by an SRA- and PKCζ-dependent mechanism to regulate TNFα. Enhancing resolution of dust-mediated lung inflammation through targeting IL-10 and/or SRA may represent new approaches to therapeutic interventions.