Vitamin E, γ-tocopherol, diminishes ex vivo basophil response to dust mite allergen.

Epidemiologic studies suggest that dietary vitamin E is a candidate intervention for atopic disease. We used in vitro and ex vivo exposures to test the hypothesis that the most common dietary isoform of vitamin E, γ-tocopherol (γT), could suppress FcεRI-mediated basophil activation. Rat basophilic leukemia (RBL)-SX38 cells that express human FcεRI were treated with or without γT, followed by stimulation with α-IgE. In the ex vivo study, 20 Der f 1-allergic volunteers consumed a γT-enriched supplement for 7 days. Their basophils were challenged ex vivo with α-IgE and graded doses of Der f 1 before and after the supplementation period. γt treatment of RBL-SX38 cells significantly reduced basophil degranulation and de novo TH2 cytokine production. Daily consumption of a γT-rich supplement by dust mite-allergic volunteers reduced basophil activation after ex vivo dust mite challenge. Vitamin E supplements rich in γT may be useful adjuncts in decreasing atopic disease.

Modulation of asthma by endotoxin.

Asthma is a common inflammatory disease triggered by both allergic and non-allergic stimuli. The most common risk factor in the development of asthma is induction of IgE against indoor allergens and imbalance in the T-helper type 1 (Th1) and Th2 with skewing towards Th2 response. Interplay of genetic and environmental factors is involved in induction and propagation of asthma. Endotoxin is a common environmental pollutant and elicits a Th1 response. The amount of endotoxin varies with several factors but of significant interest has been the role of pets. Endotoxin not only protects against the development of asthma but also enhances an already established inflammation. The difference of outcomes is likely not only due to the time and dose of exposure but also as we discuss the variable interaction of genes with environment. We focus on studies since 2001 that have explored the role of endotoxin in asthma and the gene-environment interactions of the endotoxin effect.

Effect of inhaled dust mite allergen on regional particle deposition and mucociliary clearance in allergic asthmatics.

BACKGROUND: Acute exacerbations in allergic asthmatics may lead to impaired ability to clear mucus from the airways, a key factor in asthma morbidity. OBJECTIVE: The purpose of this study was to determine the effect of inhaled house dust mite challenge on the regional deposition of inhaled particles and mucociliary clearance (MCC) in allergic asthmatics. METHODS: We used gamma scintigraphy (inhalation of (99m) Tc -sulphur colloid particles) to measure the regional particle deposition and MCC in allergic asthmatics (n=12) 4 h following an inhaled dust mite allergen challenge (Dermatophagoides farinae extract; PD(max) =fall in forced expiratory volume in 1 s of 10%) for comparison with baseline non-challenge measures. RESULTS: In responders (n=9 PD(max) dose), lung function returned to pre-challenge values by 3 h but was significantly decreased at 6 and 24 h in three of the responders (i.e. late-phase response) and induced sputum eosinophils were increased at 24 h post-challenge (P<0.05). Responders showed enhanced bronchial airway deposition of inhaled particles (P<0.05) and slowed clearance from the central lung zone (P<0.01) at 4 h post-challenge compared with the baseline (no allergen challenge) that was predicted by the PD(max) allergen concentration (r=-0.70, P<0.05). The decline in lung function at 24 h post-challenge correlated with reduced MCC from the central lung zone (r=-0.78, P<0.02) and PD(max) . Non-responders (n=3) showed no change in lung function, regional deposition or MCC post-challenge vs. baseline. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that regional deposition and clearance of inhaled particles may be sensitive for detecting mild airway obstruction associated with early- and late-phase allergen-induced effects on mucus secretions. The study was listed on clinicaltrials.gov (NCT00448851).

Is Johnny wheezing? Parent-child agreement in the Childhood Asthma in America survey.

We compared responses of children and parents to determine their level of agreement in a national, population-based survey regarding asthma-related health of US children. A telephone-based survey was conducted in 2004 among a national probability sample of children with current asthma in the United States. To compare responses between parent-child pairs, a subset of 284 children aged 10-15 were interviewed in addition to the parents. This survey collected data on asthma symptom prevalence, physical activity limitations and impact of exercise on asthma, and asthma management including medication use. Paired responses were compared using the kappa (κ) statistic. Overall, parents of 10-15-yr-olds underestimated the burden of asthma experienced by their children, especially the effects on physical activity. More than half (58%) of children replied that exercise was a trigger for their asthma compared to only 35% of parents (κ 0.23). Children were more likely than parents to mention activity limitations, specifically avoiding physical exertion (63% vs. 49%-κ 0.004). Prevalence of symptoms was also underreported by parents relative to children, particularly breathing problems (41% vs. 67%-κ 0.16) and cough (45% vs. 64%-κ 0.14). Maintenance therapy use in the past 4 weeks was reported by 35% of children, whereas 44% of parents believed their children had used maintenance therapy (κ 0.47). Relative to children's self-report, parents underestimated avoidance tactics used by their children with asthma, including exercise and physical activity self-limitation to prevent the onset or worsening of asthma symptoms. Parents also underreported asthma symptoms of their children aged 10-15 years old and were discordant with their children regarding medication use. Increasing regular communication about asthma between child, parent, and physician is warranted to improve asthma control and overall health.

In vivo uptake of inhaled particles by airway phagocytes is enhanced in patients with mild asthma compared with normal volunteers.

BACKGROUND: The uptake of inhaled particulate matter by airway phagocytes is an important defence mechanism contributing to the clearance of potentially toxic substances, including aeroallergens, from the lung. Since airway monocytes and macrophages can also function as antigen presenting cells, their ability to engulf materials deposited on the airway surface is of particular interest in patients with allergic asthma. To determine whether airway mononuclear phagocytes of patients with allergic asthma might have enhanced phagocytic activity, the in vivo uptake of inhaled radiolabelled particles was compared in 10 patients with mild allergic asthma and 8 healthy (non-allergic) individuals. METHODS: Phagocyte function was assessed by quantifying the proportion of radioactivity associated with cellular and supernatant fractions of induced sputum 2 h after inhalation of radiolabelled sulfur colloid particles. All subjects were pretreated with albuterol before sputum induction. A standardised breathing pattern was used to target aerosol deposition in the bronchial airways. RESULTS: In vivo particle uptake by airway cells was significantly greater in patients with asthma than in healthy volunteers (57.2% (95% CI 46.5% to 67.9%) vs 22.3% (95% CI 4.9% to 39.6%), p<0.01), as was in vitro phagocytosis of opsonised zymosan-A bioparticles. There was also a significant correlation (r = 0.85, p<0.01) between the percentage of sputum mononuclear phagocytes and the percentage uptake of particles in the patients with asthma but not in the control subjects. CONCLUSIONS: In vivo particle uptake by airway macrophages is enhanced in persons with mild asthma. Enhanced uptake and processing of particulate antigens could contribute to the pathogenesis and progression of allergic airways disease and may contribute to the increased risk of disease exacerbation associated with particulate exposure.

Gamma-tocopherol prevents airway eosinophilia and mucous cell hyperplasia in experimentally induced allergic rhinitis and asthma.

BACKGROUND: Traditional therapies for asthma and allergic rhinitis (AR) such as corticosteroids and antihistamines are not without limitations and side effects. The use of complementary and alternative approaches to treat allergic airways disease, including the use of herbal and dietary supplements, is increasing but their efficacy and safety are relatively understudied. Previously, we have demonstrated that gamma-tocopherol (gammaT), the primary form of dietary vitamin E, is more effective than alpha-tocopherol, the primary form found in supplements and tissue, in reducing systemic inflammation induced by non-immunogenic stimuli. OBJECTIVE: We used allergic Brown Norway rats to test the hypothesis that a dietary supplement with gammaT would protect from adverse nasal and pulmonary responses to airway allergen provocation. METHODS: Ovalbumin (OVA)-sensitized Brown Norway rats were treated orally with gammaT before intranasal provocation with OVA. Twenty-four hours after two challenges, histopathological changes in the nose, sinus and pulmonary airways were compared with gene expression and cytokine production in bronchoalveolar lavage fluid and plasma. RESULTS: We found that acute dosing for 4 days with gammaT was sufficient to provide broad protection from inflammatory cell recruitment and epithelial cell alterations induced by allergen challenge. Eosinophil infiltration into airspaces and tissues of the lung, nose, sinus and nasolacrimal duct was blocked in allergic rats treated with gammaT. Pulmonary production of soluble mediators PGE(2), LTB(4) and cysteinyl leukotrienes, and nasal expression of IL-4, -5, -13 and IFN-gamma were also inhibited by gammaT. Mucous cell metaplasia, the increase in the number of goblet cells and amounts of intraepithelial mucus storage, was induced by allergen in both pulmonary and nasal airways and decreased by treatment with gammaT. CONCLUSIONS: Acute treatment with gammaT inhibits important inflammatory pathways that underlie the pathogenesis of both AR and asthma. Supplementation with gammaT may be a novel complementary therapy for allergic airways disease.

Development of atopy and asthma: candidate environmental influences and important periods of exposure.

Atopy is a major risk factor for the development of asthma. Immune processes that lead to the development of antigen-specific IgE are essential to the development of atopy. This review examines the immune processes that are candidate targets for modulation by environmental agents; environmental and lifestyle factors that have been suggested as modulators of the development of atopy; and the impact of known environmental agents on atopic processes in the airway. The most important periods of immune development with regard to expression of atopy are likely during gestation and early childhood. A better understanding of which environmental agents are important, as well as the period of life during which these agents may exert an important effect, is essential to devising rational environmental avoidance strategies for at-risk populations.

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary.

Fetuses, infants, and juveniles (preadults) should not be considered simply "small adults" when it comes to toxicological risk. We present specific examples of developmental toxicants that are more toxic to children than to adults, focusing on effects on the immune and respiratory systems. We describe differences in both the pharmacokinetics of the developing immune and respiratory systems as well as changes in target organ sensitivities to toxicants. Differential windows of vulnerability during development are identified in the context of available animal models. We provide specific approaches to directly investigate differential windows of vulnerability. These approaches are based on fundamental developmental biology and the existence of discrete developmental processes within the immune and respiratory systems. The processes are likely to influence differential developmental susceptibility to toxicants, resulting in lifelong toxicological changes. We also provide a template for comparative research. Finally, we discuss the application of these data to risk assessment.

Airway response to concomitant exposure with endotoxin and allergen in atopic asthmatics.

Epidemiological and in vivo studies suggest that inhaled endotoxin may be an important environmental factor associated with the increases in asthma-related morbidity and mortality. Recent studies by our group and others provide a rationale for the hypothesis that airway exposure of atopic asthmatics to both allergen and endotoxin might result in greater inflammatory responses than those observed with either stimulus alone. Moreover, these studies may provide further evidence that concomitant exposure to allergen and endotoxin is an important factor in asthma pathogenesis.

Effect of air pollution in asthma and respiratory allergy.

Epidemiologic and controlled exposure studies of human volunteers have shown that exposure to a variety of pollutants induces asthma exacerbations. Interestingly, in the case of ozone, recent evidence suggests that this pollutant acts to enhance the effect of inhaled allergen in persons with asthma. These and other data also suggest that pollutants may influence lung function in persons with asthma by increasing airway inflammation. The interaction of pollutants and inhaled allergens and the effect of pollutant exposure on baseline airway inflammation may be a key mechanism of pollutant-induced exacerbation of asthma. Further study of this interaction, as well as interactions of multiple pollutants, will be crucial for rational development of intervention and regulatory strategies.

Ozone effects on the immediate-phase response to allergen in the nasal airways of allergic asthmatic subjects.

Epidemiologic and clinical trials have suggested that exposure to ozone increases airway hyperresponsiveness and inflammatory response to inhaled nasal allergen challenge in allergic asthmatic subjects. Previous studies have demonstrated an increased late-phase response to nasal allergen challenge; however, the early-phase response is unknown. We sought to characterize the early-phase response by measuring mast-cell inflammatory mediators and cellular influx at time points immediately following ozone exposure and subsequent allergen challenge. A cohort of mild, asymptomatic dust mite--sensitive asthmatic subjects was identified. Each subject underwent two separate exposures to both 0.4 ppm ozone and clean air in a randomized manner. Nasal lavage was performed before and after each exposure. Nasal allergen was then administered to a defined clinical end point, followed by nasal lavage. Differential cell counts and mast-cell products were identified in each lavage specimen. The mast-cell mediators tryptase and prostaglandin D2 were analyzed, as was a marker of epithelial cell permeability, albumin. Although allergen produced an increase in early-onset mediator release (mast cell-derived), no enhancement was noted after exposure to ozone. Neutrophil and eosinophil inflammatory mediators were not increased after ozone exposure or enhanced after allergen exposure, although ozone did enhance eosinophilic influx after exposure to allergen. Ozone exposure does not promote early-phase--response mediator release or enhance the response to allergen challenge in the nasal airways of extrinsic asthmatic subjects. Ozone, however, may promote an inflammatory cell influx, which helps induce a more significant late-phase response in this population.

Mechanisms of pollution-induced airway disease: in vivo studies.

Several studies have investigated the effects of ozone, sulphur dioxide (SO2), and nitrogen dioxide (NO2) on lung function in normal and asthmatic subjects. Decreased lung function has been observed with ozone levels as low as 0.15 ppm-this effect is concentration dependent and is exacerbated by exercise. A number of lines of evidence suggest that the effect on lung function is mediated, at least in part, by neural mechanisms. In both normals and asthmatics, ozone has been shown to induce neutrophilic inflammation, with increased levels of several inflammatory mediators, including prostaglandin E2. However, in normal subjects, none of the markers of inflammation correlate with changes in lung function. The lung function changes in asthmatics may be associated with inflammatory effects; alternatively, ozone may prime the airways for an increased response to subsequently inhaled allergen. Indeed, an influx of both polymorphonucleocytes and eosinophils has been observed in asthmatic patients after ozone exposure. It has been suggested that the effect of ozone on classic allergen-induced bronchoconstriction may be more significant than any direct effect of this pollutant in asthmatics. SO2 does not appear to affect lung function in normal subjects, but may induce bronchoconstriction in asthmatics. Nasal breathing, which is often impaired in asthmatics, reduces the pulmonary effects of SO2, since this water-soluble gas is absorbed by the nasal mucosa. NO2 may also influence lung function in asthmatics, but further research is warranted. SO2 and NO2 alone do not seem to have a priming effect in asthmatics, but a combination of these two gases has resulted in a heightened sensitivity to subsequently inhaled allergen.

Effect of pollutants in rhinitis.

Allergic rhinitis is a very common disease worldwide and is influenced by both genetic and environmental factors. Exposure to environmental allergens is the most significant environmental factor in development and exacerbation of allergic rhinitis. However, air pollutants that are not allergens may affect allergic inflammation in the nasal airway. The nasal airway possesses a number of defense mechanisms to deal with environmental irritants. This article examines the effect of ozone and particulate air pollution of TH2-type inflammation in the airway and how nasal defenses protect the upper and lower airway from adverse effects of pollutants.

Air pollution in asthma: effect of pollutants on airway inflammation.

OBJECTIVES: The objective of this review is to examine the impact of air pollutants on airway inflammation, with an emphasis on the interaction of the effect of ozone, particulate matter, and endotoxin exposure and immunoglobulin E-mediated airway inflammation. DATA SOURCES: This review examines the National Ambient Air Quality Standards and sources for different types of air pollution, as well as undertakes a review of epidemiologic and human challenge studies which address the impact of air contaminants in asthma and allergic inflammation. RESULTS: Epidemiologic and human challenge studies both demonstrate that ozone and endotoxin exposure can exacerbate allergic inflammation in the airway. Conversely, allergic processes may enhance individual response to air pollutants as well. CONCLUSIONS: Ozone and particulate matter are both important agents in inducing asthma exacerbation. However, these pollutants have not been implicated in development of immunoglobulin E responses to neoantigens. Decreased exposure to these pollutants or a better understanding of the processes by which they impact the airway may be useful in decreasing asthma severity.

Modulation of mast cell functions by in vitro ozone exposure.

Exposure to ozone has been reported to cause increased immediate bronchial reactivity to inhaled allergen in asthmatics. The purpose of these studies was to determine whether ozone induces either spontaneous physiological degranulation or enhanced immunoglobulin E (IgE)-mediated degranulation of mast cells, thus accounting for the in vivo effects noted in asthmatics. A rat mast cell line (RBL-2H3) was exposed to different levels of ozone (0.1, 0.3, 0.5, and 1.0 ppm), covered by different amounts of buffer, and both cytotoxic and nontoxic exposure conditions were determined. In addition to cytotoxicity, spontaneous release of granule products and prostaglandin D2 (PGD2) associated with ozone exposure were assessed. RBL-2H3 cells were also exposed to ozone under noncytotoxic conditions followed by stimulation with alpha-IgE to cross-link membrane-bound IgE and A23187 so that the effect of ozone on stimulated degranulation could be examined. Only exposure conditions associated with cytotoxicity were associated with spontaneous release of mast cell serotonin, indicating no physiologic degranulation due to ozone exposure. Data presented herein also demonstrate that ozone substantially inhibited both IgE- and A23187-induced degranulation. Neither catalase nor superoxide dismutase protected cells from the inhibitory effect of ozone, indicating that ozone does not act through generation of H2O2 or superoxide. Additionally, ozone caused a modest increase in spontaneous PGD2 generation only under cytotoxic conditions. Thus ozone appears to inhibit mast cell degranulation after IgE- or A23187-mediated stimulation and causes direct release of mast cell granule products and PGD2 only under conditions associated with membrane cytotoxicity.

Allergen provocation augments endotoxin-induced nasal inflammation in subjects with atopic asthma.

BACKGROUND: Recent epidemiologic and in vivo studies have suggested that inhaled endotoxin plays an important role in asthma pathogenesis. OBJECTIVE: The present study examines the effect of nasal allergen provocation on subsequent endotoxin challenge in subjects with atopic asthma. METHODS: By using a split-nose randomized crossover design, individual nares of 12 asthmatic subjects underwent challenge and lavage as follows. Immediately after a baseline nasal lavage, one nares received normal saline, and the other received dust mite antigen. Four hours later, both nares were exposed to either saline or endotoxin. Dust mite antigen (Dermatophagoides farinae) and endotoxin (Escherichia coli 026:B6) doses were 100 AU and 1000 ng, respectively. Postchallenge lavages were done at 8 and 24 hours after the initial challenge. The subjects then returned a minimum of 3 weeks later for crossover to the study arm. Nasal lavage fluid was analyzed for total and differential cell counts, IL-8, IL-6, intercellular adhesion molecule 1, GM-CSF, eosinophil cationic protein, myeloperoxidase, and soluble CD14. RESULTS: A significant increase in the total inflammatory cell count was seen at 8 hours for the dust mite/endotoxin exposure compared with the saline/saline and saline/endotoxin exposures. Differential cell counts revealed a similar neutrophilic and eosinophilic inflammation for the dust mite/endotoxin exposure at 8 hours. CONCLUSIONS: These data demonstrate an interaction between allergen and endotoxin exposure in asthmatic subjects, suggesting that a prior allergen challenge significantly augments the endotoxin-induced inflammation. Moreover, these data provide further evidence that concomitant exposure to allergen and endotoxin may be an important factor in asthma pathogenesis.

Blunting airway eosinophilic inflammation results in a decreased airway neutrophil response to inhaled LPS in patients with atopic asthma: a role for CD14.

Recent data demonstrate that atopic inflammation might enhance airway responses to inhaled LPS in individuals with atopic asthma by increasing CD14 expression on airway macrophages. We sought to determine whether blunting airway eosinophilic inflammation decreases CD14 expression and the subsequent airway polymorphonuclear neutrophil (PMN) response to inhaled LPS in subjects with atopic asthma. Twelve such subjects underwent a 2-week, placebo-controlled trial of inhaled steroid (440 microg fluticasone propionate [FP] twice per day); this was followed 48 hours later by an inhaled LPS (5 microg) challenge. A comparison of LPS-induced inflammatory cells in sputum, CD14 expression, and methacholine responsiveness with FP or placebo was conducted. Flow cytometry was used to analyze membrane-bound CD14 expression (mean fluorescence intensity) on sputum macrophages. We report that 48 hours before inhaled LPS challenge (baseline), FP significantly blunted airway eosinophils (cells per milligram; P =.04) and mCD14 expression (mean fluorescence intensity; P =.03) but did not decrease the number of PMNs (cells per milligram). Six hours after LPS challenge, airway PMNs and mCD14 expression were significantly decreased for FP in comparison with placebo (P =.04). Our data suggest that decreasing airway allergic inflammation with corticosteroids results in both decreased expression of CD14 on airway monocytic cells and a decreased PMN response to inhaled LPS.

Ozone exposure has both a priming effect on allergen-induced responses and an intrinsic inflammatory action in the nasal airways of perennially allergic asthmatics.

Ozone may play a significant role in the exacerbation of airway disease in asthmatics, either by priming the airway mucosa such that cellular responses to allergen are enhanced or by exerting an intrinsic effect on airway inflammation. Previous investigations of nonasthmatic subjects revealed that ozone induces both nasal and bronchial inflammation, suggesting that nasal responses to ozone may be used as a surrogate marker for the effect of this pollutant on bronchial mucosal inflammation. In this study, the effect of exposure to 0.4 ppm ozone on nasal inflammation in 11 allergic asthmatics sensitive to Dermatophygoides farinae was examined. This study was designed such that the effect of ozone exposure on the late-phase reaction to allergen was emphasized, using eosinophil influx and changes in eosinophil cationic protein as principal endpoints. By employing a "split-nose" design, in which allergen was applied to only one side of the nose while saline was applied to the contralateral side, both the effect of ozone on nasal inflammation due to allergen challenge as well as its direct action on non-allergen-challenged nasal tissues was examined. The results reported herein indicate that ozone exposure has both a priming effect on allergen-induced responses as well as an intrinsic inflammatory action in the nasal airways of perennially allergic asthmatics.

Prolonged acute exposure to 0.16 ppm ozone induces eosinophilic airway inflammation in asthmatic subjects with allergies.

BACKGROUND: Increased ambient ozone levels have been associated with increased asthma morbidity in epidemiologic studies. Given that asthma is characterized by airway inflammation and increased sensitivity to airway irritants, it has been suggested that asthmatic subjects may be particularly sensitive to the effect of ozone. OBJECTIVE: The objective of this study was to determine whether exposure to 0.16 ppm ozone induces eosinophilic inflammation in the lower airways of asthmatic subjects. METHODS: Eight asthmatic subjects sensitive to mites were exposed to 0.16 ppm ozone and clean air on separate occasions no less than 4 weeks apart in a double-blind, randomized fashion followed by bronchoscopy 18 hours later. Bronchoalveolar lavage fluid and bronchial lavage fluid were examined for eosinophils. RESULTS: Ozone induced significant increases in airway eosinophils, especially in bronchial lavage fluid. CONCLUSIONS: Ozone exposure results in increased eosinophilic inflammation in the lower airways of asthmatic subjects with allergies.