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Inactivation of common airborne antigens by perfluoroalkyl chemicals modulates early life allergic asthma.

ABSTRACT: Allergic asthma, driven by T helper 2 cell-mediated immune responses to common environmental antigens, remains the most common respiratory disease in children. Perfluorinated chemicals (PFCs) are environmental contaminants of great concern, because of their wide application, persistence in the environment, and bioaccumulation. PFCs associate with immunological disorders including asthma and attenuate immune responses to vaccines. The influence of PFCs on the immunological response to allergens during childhood is unknown. We report here that a major PFC, perfluorooctane sulfonate (PFOS), inactivates house dust mite (HDM) to dampen 5-wk-old, early weaned mice from developing HDM-induced allergic asthma. PFOS further attenuates the asthma protective effect of the microbial product lipopolysaccharide (LPS). We demonstrate that PFOS prevents desensitization of lung epithelia by LPS, thus abolishing the latter's protective effect. A close mechanistic study reveals that PFOS specifically binds the major HDM allergen Der p1 with high affinity as well as the lipid A moiety of LPS, leading to the inactivation of both antigens. Moreover, PFOS at physiological human (nanomolar) concentrations inactivates Der p1 from HDM and LPS in vitro, although higher doses did not cause further inactivation because of possible formation of PFOS aggregates. This PFOS-induced neutralization of LPS has been further validated in primary human cell models and extended to an in vivo bacterial infection mouse model. This study demonstrates that early life exposure of mice to a PFC blunts airway antigen bioactivity to modulate pulmonary inflammatory responses, which may adversely affect early pulmonary health.

SUBMITTER: Wang M

PROVIDER: S-EPMC8214667 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Perfluoroalkyl chemicals and asthma among children 12-19 years of age: NHANES (1999-2008).

Project description:BackgroundPerfluoroalkyl chemicals (PFCs) are a family of commonly used industrial chemicals whose persistence and ubiquity in human blood samples has led to concern about possible toxicity. Several animal studies and one recent human study have suggested a link between exposure to PFCs and asthma, although few epidemiologic studies have been conducted.ObjectivesWe investigated children's PFC serum concentrations and their associations with asthma-related outcomes.MethodsWe evaluated the association between serum concentrations of eight PFCs, including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), with self-reported lifetime asthma, recent wheezing, and current asthma using data from participants 12-19 years of age from the 1999-2000 and 2003-2008 National Health and Nutrition Examination Surveys.ResultsIn multivariable-adjusted models, PFOA was associated with higher odds of ever having received a diagnosis of asthma [odds ratio (OR) = 1.18; 95% CI: 1.01, 1.39 for a doubling in PFOA], whereas for PFOS there were inverse relationships with both asthma and wheezing (OR = 0.88; 95% CI: 0.74, 1.04, and OR = 0.83; 95% CI: 0.67, 1.02, respectively). The associations were attenuated after accounting for sampling weights. No associations were seen between the other PFCs and any outcome.ConclusionsThis cross-sectional study provides some evidence for associations between exposure to PFCs and asthma-related outcomes in children. The evidence is inconsistent, however, and prospective studies are needed.

| S-EPMC4181915 | biostudies-literature

Indoor metabolites and chemicals outperform microbiome in classifying childhood asthma and allergic rhinitis.

Project description:Indoor microorganisms impact asthma and allergic rhinitis (AR), but the associated microbial taxa often vary extensively due to climate and geographical variations. To provide more consistent environmental assessments, new perspectives on microbial exposure for asthma and AR are needed. Home dust from 97 cases (32 asthma alone, 37 AR alone, 28 comorbidity) and 52 age- and gender-matched controls in Shanghai, China, were analyzed using high-throughput shotgun metagenomic sequencing and liquid chromatography-mass spectrometry. Homes of healthy children were enriched with environmental microbes, including Paracoccus, Pseudomonas, and Psychrobacter, and metabolites like keto acids, indoles, pyridines, and flavonoids (astragalin, hesperidin) (False Discovery Rate < 0.05). A neural network co-occurrence probability analysis revealed that environmental microorganisms were involved in producing these keto acids, indoles, and pyridines. Conversely, homes of diseased children were enriched with mycotoxins and synthetic chemicals, including herbicides, insecticides, and food/cosmetic additives. Using a random forest model, characteristic metabolites and microorganisms in Shanghai homes were used to classify high and low prevalence of asthma/AR in an independent dataset in Malaysian schools (N = 1290). Indoor metabolites achieved an average accuracy of 74.9% and 77.1% in differentiating schools with high and low prevalence of asthma and AR, respectively, whereas indoor microorganisms only achieved 51.0% and 59.5%, respectively. These results suggest that indoor metabolites and chemicals rather than indoor microbiome are potentially superior environmental indicators for childhood asthma and AR. This study extends the traditional risk assessment focusing on allergens or air pollutants in childhood asthma and AR, thereby revealing potential novel intervention strategies for these diseases.

| S-EPMC10902507 | biostudies-literature

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Project description:Urban children with asthma and allergic rhinitis (AR) are at risk for experiencing worse AR-related quality of life (QOL). Although AR may be underdiagnosed and undertreated in urban minority children, research has not considered which illness-related indicators (eg, AR control) may contribute to AR QOL in this population.To examine associations among AR control, asthma control, allergy symptoms, asthma symptoms, and AR QOL in a sample of 195 urban caregivers and their children with asthma (7-9 years of age) from African American, Latino, and non-Latino white backgrounds. Racial and ethnic differences in AR QOL were also examined.Families resided in 1 of 4 cities selected as recruitment sources because of their high concentrations of ethnic minority and non-Latino white, urban families. Caregivers and children completed a series of interview-based and clinician-based assessments across one academic year and 4-week periods to track daily asthma and nasal symptoms.Better AR control was associated with higher AR QOL (? = -.32, P < .01) and all QOL subscales. AR control predicted AR QOL over and above asthma control (? = -.28, P < .01). Controlling for AR control, non-Latino white children reported better QOL related to practical problems than both Latino and African American children (P < .05).Findings suggest that strategies to enhance AR control in urban children with asthma may assist in improving AR QOL. Non-Latino white children may experience less impairment of their AR QOL because of practical problems (eg, blow nose) than African American or Latino children with asthma.

| S-EPMC4014066 | biostudies-literature

Tissue inhibitor of metalloproteinase-1 modulates allergic lung inflammation in murine asthma.

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| S-EPMC2676334 | biostudies-literature

LPS inactivation by a host lipase allows lung epithelial cell sensitization for allergic asthma.

Project description:Allergic asthma is a chronic inflammatory disease primarily mediated by Th2 immune mechanisms. Numerous studies have suggested that early life exposure to lipopolysaccharide (LPS) is negatively associated with allergic asthma. One proposed mechanism invokes desensitization of lung epithelial cells by LPS. We report here that acyloxyacyl hydrolase (AOAH), a host lipase that degrades and inactivates LPS, renders mice more susceptible to house dust mite (HDM)-induced allergic asthma. Lung epithelial cells from Aoah-/- mice are refractory to HDM stimulation, decreasing dendritic cell activation and Th2 responses. Antibiotic treatment that diminished commensal LPS-producing bacteria normalized Aoah-/- responses to HDM, while giving LPS intrarectally ameliorated asthma. Aoah-/- mouse feces, plasma, and lungs contained more bioactive LPS than did those of Aoah+/+ mice. By inactivating commensal LPS, AOAH thus prevents desensitization of lung epithelial cells. An enzyme that prevents severe lung inflammation/injury in Gram-negative bacterial pneumonia has the seemingly paradoxical effect of predisposing to a Th2-mediated airway disease.

| S-EPMC6122967 | biostudies-literature

Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma.

Project description:Allergic asthma rates have increased steadily in developed countries, arguing for an environmental aetiology. To assess the influence of gut microbiota on experimental murine allergic asthma, we treated neonatal mice with clinical doses of two widely used antibiotics--streptomycin and vancomycin--and evaluated resulting shifts in resident flora and subsequent susceptibility to allergic asthma. Streptomycin treatment had little effect on the microbiota and on disease, whereas vancomycin reduced microbial diversity, shifted the composition of the bacterial population and enhanced disease severity. Neither antibiotic had a significant effect when administered to adult mice. Consistent with the 'hygiene hypothesis', our data support a neonatal, microbiota-driven, specific increase in susceptibility to experimental murine allergic asthma.

| S-EPMC3343350 | biostudies-literature

Sensitization to Airborne Fungal Allergens Associates with Asthma and Allergic Rhinitis Presentation and Severity in the Singaporean/Malaysian Population.

Project description:Fungal spores and conidia are the major components of total airspora in the tropical Asia environment, and their sensitization patterns are often associated with allergic diseases such as asthma, allergic rhinitis (AR), and atopic dermatitis. Hence, we recruited a cross-sectional cohort of 9223 Singapore/Malaysia Chinese adults and assessed their sensitization against Curvularia lunata allergen using the skin prick test approach. A subset of this cohort (n = 254) was also screened for specific Immunoglobulin E (sIgE) titers against a panel of 11 fungal allergens. We found significant association of Curvularia lunata sensitization with the risk of asthma (OR = 1.66, 95% CI: 1.17-2.33; p = 0.00391) and AR (OR = 1.69, 95% CI: 1.18-2.41; p = 0.00396). Among asthmatic patients (n = 1680), Curvularia lunata sensitization also increased frequencies of wheezing symptoms (OR = 1.81, 95% CI: 1.05-2.96; p = 0.0239), general practitioner/specialist visits (OR = 2.37, 95% CI: 1.13-4.61; p = 0.0157), and other asthma-related exacerbation events (OR = 2.14, 95% CI: 1.04-4.10; p = 0.0289). In our serum cohort, sensitization to Aspergillus spp. was the most common fungal sensitization, with 23.6% (n = 60) had a class 3 and above sensitization (positive sensitization; sIgE titers of > 3.5 kU/L) against this allergen. Increasing sIgE titer against Aspergillus spp. was also correlated with increased AR risk and AR-related symptoms. In conclusion, our findings emphasize an important role of fungal sensitization in the manifestations of asthma and AR in the Southeast Asian Chinese population.

| S-EPMC8536550 | biostudies-literature

Real-life Effectiveness of Omalizumab in Patients with Severe Allergic Asthma: RELIEF Study.

Project description:IntroductionPatients with severe allergic asthma (SAA) are at risk of severe exacerbations. Omalizumab is recommended as an add-on treatment for patients with uncontrolled SAA, despite high-dose inhaled corticosteroids and long acting β2-agonist combination therapy (standard therapy).RELIEF was a prospective, open label, multicenter study conducted to assess the real-life effectiveness of omalizumab co-administered with standard therapy in patients with SAA for 24 months.MethodsA total of 347 patients aged ≥ 6 years with SAA were enrolled, 285 of whom (8 pediatrics and 277 adolescents and adults) completed this 24-month study. Compared with the 12 months prior to baseline, the mean number of exacerbations was reduced in the overall population at any time interval during the study. Proportion of patients with no exacerbations increased to 77.7% at 24 months from 32.6% at 12 months prior to baseline. A reduction in healthcare resource utilization was also observed. The mean number of specialist visits reduced from baseline (5.8 visits) to 2.4 visits at Month 24.ResultsThe mean asthma control test score was >19 at every time-point during the study. The rate of Global Evaluation of Treatment Effectiveness (GETE) for asthma response significantly increased at Months 18 and 24 (P <0.05) compared to baseline. Pulmonary function remained relatively stable for the overall study population. There were no new or unexpected safety findings in the study.ConclusionRELIEF study showed that add-on therapy with omalizumab is effective in reducing exacerbations, healthcare utilization, and improving GETE score in patients with SAA uncontrolled by standard therapy.

| S-EPMC10156055 | biostudies-literature

Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life.

Project description:Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene a disintegrin and metalloprotease 33 (ADAM33) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33-null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances postnatal airway eosinophilia and bronchial hyperresponsiveness following subthreshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma.

| S-EPMC4968941 | biostudies-literature

Evaluation of the experimental basis for assessment factors to protect individuals with asthma from health effects during short-term exposure to airborne chemicals.

Project description:BackgroundAsthmatic individuals constitute a large sub-population that is often considered particularly susceptible to the deleterious effects of inhalation of airborne chemicals. However, for most such chemicals information on asthmatics is lacking and inter-individual assessment factors (AFs) of 3-25 have been proposed for use in the derivation of health-based guideline values.ObjectiveTo evaluate available information in attempt to determine whether a general difference in airway response during short-term exposure between healthy and asthmatic individuals can be identified, and whether current AFs for inter-individual variability provide sufficient protection for asthmatics.MethodsAfter performing systematic review of relevant documents and the scientific literature estimated differential response factors (EDRF) were derived as the ratio between the lowest observed adverse effect levels for healthy and asthmatic subjects based on studies in which both groups were tested under the same conditions. Thereafter, the concentration-response relationships for healthy and asthmatic subjects exposed separately to four extensively tested chemicals (nitrogen dioxide, ozone, sulfuric acid, sulfur dioxide) were compared on the basis of combined data. Finally, a Benchmark Concentration (BMC) analysis was performed for sulfur dioxide.ResultsWe found evidence of higher sensitivity among asthmatics (EDRF > 1) to 8 of 19 tested chemicals, and to 3 of 11 mixtures. Thereafter, we confirmed the higher sensitivity of asthmatics to sulfuric acid and sulfur dioxide. No difference was observed in the case of ozone and nitrogen dioxide. Finally, our BMC analysis of sulfur dioxide indicated a ninefold higher sensitivity among asthmatics.ConclusionAlthough experimental data are often inconclusive, our analyses suggest that an AF of 10 is adequate to protect asthmatics from the deleterious respiratory effects of airborne chemicals.

| S-EPMC4819830 | biostudies-literature

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