Dataset Information

Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression.

ABSTRACT: Elevated levels of combustion-derived particulate matter (CDPM) are a risk factor for the development of lung diseases such as asthma. Studies have shown that CDPM exacerbates asthma, inducing acute lung dysfunction and inflammation; however, the impact of CDPM exposure on early immunological responses to allergens remains unclear. To determine the effects of early-life CDPM exposure on allergic asthma development in infants, we exposed infant mice to CDPM and then induced a mouse model of asthma using house dust mite (HDM) allergen. Mice exposed to CDPM+HDM failed to develop a typical asthma phenotype including airway hyper-responsiveness, T-helper type 2 (Th2) inflammation, Muc5ac expression, eosinophilia, and HDM-specific immunoglobulin (Ig) compared with HDM-exposed mice. Although HDM-specific IgE was attenuated, total IgE was twofold higher in CDPM+HDM mice compared with HDM mice. We further demonstrate that CDPM exposure during early life induced an immunosuppressive environment in the lung, concurrent with increases in tolerogenic dendritic cells and regulatory T cells, resulting in the suppression of Th2 responses. Despite having early immunosuppression, these mice develop severe allergic inflammation when challenged with allergen as adults. These findings demonstrate a mechanism whereby CDPM exposure modulates adaptive immunity, inducing specific antigen tolerance while amplifying total IgE, and leading to a predisposition to develop asthma upon rechallenge later in life.

SUBMITTER: Saravia J

PROVIDER: S-EPMC3999175 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression.

Saravia J J You D D Thevenot P P Lee G I GI Shrestha B B Lomnicki S S Cormier S A SA

Mucosal immunology 20131030 3

Elevated levels of combustion-derived particulate matter (CDPM) are a risk factor for the development of lung diseases such as asthma. Studies have shown that CDPM exacerbates asthma, inducing acute lung dysfunction and inflammation; however, the impact of CDPM exposure on early immunological responses to allergens remains unclear. To determine the effects of early-life CDPM exposure on allergic asthma development in infants, we exposed infant mice to CDPM and then induced a mouse model of asthm ...[more]

PMID: 24172848

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Project description:BackgroundPollutant particles containing environmentally persistent free radicals (EPFRs) are formed during many combustion processes (e.g. thermal remediation of hazardous wastes, diesel/gasoline combustion, wood smoke, cigarette smoke, etc.). Our previous studies demonstrated that acute exposure to EPFRs results in dendritic cell maturation and Th17-biased pulmonary immune responses. Further, in a mouse model of asthma, these responses were enhanced suggesting exposure to EPFRs as a risk factor for the development and/or exacerbation of asthma. The aryl hydrocarbon receptor (AHR) has been shown to play a role in the differentiation of Th17 cells. In the current study, we determined whether exposure to EPFRs results in Th17 polarization in an AHR dependent manner.ResultsExposure to EPFRs resulted in Th17 and IL17A dependent pulmonary immune responses including airway neutrophilia. EPFR exposure caused a significant increase in pulmonary Th17 cytokines such as IL6, IL17A, IL22, IL1β, KC, MCP-1, IL31 and IL33. To understand the role of AHR activation in EPFR-induced Th17 inflammation, A549 epithelial cells and mouse bone marrow-derived dendritic cells (BMDCs) were exposed to EPFRs and expression of Cyp1a1 and Cyp1b1, markers for AHR activation, was measured. A significant increase in Cyp1a1 and Cyp1b1 gene expression was observed in pulmonary epithelial cells and BMDCs in an oxidative stress and AHR dependent manner. Further, in vivo exposure of mice to EPFRs resulted in oxidative stress and increased Cyp1a1 and Cyp1b1 pulmonary gene expression. To further confirm the role of AHR activation in pulmonary Th17 immune responses, mice were exposed to EPFRs in the presence or absence of AHR antagonist. EPFR exposure resulted in a significant increase in pulmonary Th17 cells and neutrophilic inflammation, whereas a significant decrease in the percentage of Th17 cells and neutrophilic inflammation was observed in mice treated with AHR antagonist.ConclusionExposure to EPFRs results in AHR activation and induction of Cyp1a1 and in vitro this is dependent on oxidative stress. Further, our in vivo studies demonstrated a role for AHR in EPFR-induced pulmonary Th17 responses including neutrophilic inflammation.

Project description:ImportanceExposure to particulate matter (PM) has been associated with childhood asthma and wheeze. However, the specific associations between asthma and PM with an aerodynamic equivalent diameter of 1 μm or less (ie, PM1), which is a contributor to PM2.5 and potentially more toxic than PM2.5, remain unclear.ObjectiveTo investigate the association of early-life (prenatal and first year) exposure to size-segregated PM, including PM1, PM1-2.5, PM2.5, PM2.5-10, and PM10, with childhood asthma and wheeze.Design, setting, and participantsThis cross-sectional study was based on a questionnaire administered between June 2019 and June 2020 to caregivers of children aged 3 to 6 years in 7 Chinese cities (Wuhan, Changsha, Taiyuan, Nanjing, Shanghai, Chongqing, and Urumqi) as the second phase of the China, Children, Homes, Health study.ExposuresExposure to PM1, PM1-2.5, PM2.5, PM2.5-10, and PM10 during the prenatal period and first year of life.Main outcomes and measuresThe main outcomes were caregiver-reported childhood asthma and wheeze. A machine learning-based space-time model was applied to estimate early-life PM1, PM2.5, and PM10 exposure at 1 × 1-km resolution. Concentrations of PM1-2.5 and PM2.5-10 were calculated by subtracting PM1 from PM2.5 and PM2.5 from PM10, respectively. Multilevel (city and child) logistic regression models were applied to assess associations.ResultsOf 29 418 children whose caregivers completed the survey (15 320 boys [52.1%]; mean [SD] age, 4.9 [0.9] years), 2524 (8.6%) ever had wheeze and 1161 (3.9%) were diagnosed with asthma. Among all children, 18 514 (62.9%) were breastfed for more than 6 months and 787 (2.7%) had parental history of atopy. A total of 22 250 children (75.6%) had a mother with an educational level of university or above. Of the 25 422 children for whom information about cigarette smoking exposure was collected, 576 (2.3%) had a mother who was a current or former smoker during pregnancy and 7525 (29.7%) had passive household cigarette smoke exposure in early life. Early-life PM1, PM2.5, and PM10 exposure were significantly associated with increased risk of childhood asthma, with higher estimates per 10-μg/m3 increase in PM1 (OR, 1.55; 95% CI, 1.27-1.89) than in PM2.5 (OR, 1.14; 95% CI, 1.03-1.26) and PM10 (OR, 1.11; 95% CI, 1.02-1.20). No association was observed between asthma and PM1-2.5 exposure, suggesting that PM1 rather than PM1-2.5 contributed to the association between PM2.5 and childhood asthma. There were significant associations between childhood wheeze and early-life PM1 exposure (OR, 1.23; 95% CI, 1.07-1.41) and PM2.5 exposure (OR, 1.08; 95% CI, 1.01-1.16) per 10-μg/m3 increase in PM1 and PM2.5, respectively.Conclusions and relevanceIn this cross-sectional study, higher estimates were observed for the association between PM with smaller particles, such as PM1, vs PM with larger particles and childhood asthma. The results suggest that the association between PM2.5 and childhood asthma was mainly attributable to PM1.

Project description:BackgroundExposure to particulate matter <2.5 μm in diameter (PM2.5) and environmental tobacco smoke (ETS) are associated with respiratory morbidity starting in utero. However, their potential synergistic effects have not been completely elucidated. Here, we examined the joint effects of prenatal and early life PM2.5 and prenatal ETS exposure on respiratory outcomes in children.Material and methodsWe studied 536 mother-child dyads in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study in Mexico City. Exposure to PM2.5 was estimated using residence in pregnancy and child's first year of life with a satellite-based spatio-temporal model. ETS exposure was assessed by caregiver's report of any smoker in the household during the second or third trimester. Outcomes included report of ever wheeze and wheeze in the past 12 months (current wheeze) assessed when children were 6-8 years old considered in separate models. Associations were modeled using distributed lag models (DLM) with daily PM2.5 averages for pregnancy and the first year of life, adjusting for child's sex, birth weight z-score, mother's age and education at enrollment, maternal asthma, season of conception and stratified by prenatal ETS exposure (yes/no).ResultsWe identified a sensitive window from gestational week 14 through postnatal week 18 during which PM2.5 was associated with higher risk of ever wheeze at age 6-8 years. We also observed a critical window of PM2.5 exposure between postnatal weeks 6-39 and higher risk of current wheeze. We found significant associations between higher prenatal and early life PM2.5 exposure and higher cumulative risk ratios of ever wheeze (RR:3.76, 95%CI [1.41, 10.0] per 5 μg/m3) and current wheeze in the past year (RR:7.91, 95%CI [1.5, 41.6] per 5 μg/m3) only among children born to mothers exposed to ETS in pregnancy when compared to mothers who were not exposed.ConclusionsExposure to prenatal ETS modified the association between prenatal and early life PM2.5 exposure and respiratory outcomes at age 6-8 years. It is important to consider concurrent chemical exposures to more comprehensively characterize children's environmental risk. Interventions aimed at decreasing passive smoking might mitigate the effects of ambient air pollution.

Dataset Information

Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression.

Publications

Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression.

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