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Biomedical subjects

D B Peden

Publications and source records attributed to D B Peden.

At least 19 recordsLinked to original sources
PubMed2001

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 Pollutants↗
PubMed2001

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.

Air Pollutants↗
PubMed2001

CD14-dependent airway neutrophil response to inhaled LPS: role of atopy.

BACKGROUND: Inhaled endotoxin (LPS) is associated with airway neutrophilic (PMN) inflammation in both asthmatic and control subjects, with asthmatic subjects demonstrating possibly higher sensitivity. CD14 is the principal receptor mediating LPS responses in vivo. It is unknown whether constitutive CD14 can predict the magnitude of the PMN response after LPS inhalation and whether atopy plays a role in this response. OBJECTIVE: We sought to examine associations between constitutive airway CD14 expression and LPS-induced PMNs after 5 microg of LPS inhalation and to examine associations between markers of atopy (eosinophils and eosinophil cationic protein) and CD14 expression and LPS-induced PMNs. METHODS: Ten atopic asthmatic subjects and 8 healthy control subjects inhaled 0.9% saline and LPS (Escherichia coli 026:B6, 5 microg) separated by 3 weeks. Induced sputum was collected at 24 hours before and 6 hours after inhalation. Induced sputum was analyzed for total and differential cell counts and soluble markers (soluble [s]CD14, eosinophil cationic protein, IL8, and total protein). Flow cytometry was used to analyze membrane-bound CD14 expression. RESULTS: Significant associations were found between the LPS-induced PMN response (PMNs per milligram of sputum) and both constitutive sCD14 (R = 0.7, P =.005) and membrane-bound CD14 (R = 0.9, P =.01). Asthmatic subjects demonstrated significantly higher levels of constitutive sCD14 compared with control subjects, and baseline eosinophils were significantly associated with baseline sCD14 (R = 0.7, P =.01) and LPS-induced PMNs (R = 0.6, P =.03). CONCLUSION: Constitutive airway CD14 expression can predict the magnitude of the PMN response after inhaled LPS. Atopy appears to play a role in the level of CD14 expression and may contribute to LPS sensitivity in asthmatic subjects.

Administration, Inhalation↗
PubMed2001

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.

Adult↗
PubMed2000

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.

Allergens↗
PubMed2000

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.

Adult↗
PubMed2000

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.

Asthma↗
PubMed2000

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.

Child↗
PubMed1999

Increased specific airway reactivity of persons with mild allergic asthma after 7.6 hours of exposure to 0.16 ppm ozone.

BACKGROUND: Exposure to ozone causes decrements in lung function, increased airway reactivity to nonspecific bronchoconstrictors, and lung inflammation. Epidemiology studies show an association between ambient oxidant levels and increased asthma attacks and hospital admissions. OBJECTIVE: The purpose of our study was to evaluate the response of persons with mild asthma to inhaled allergen after ozone exposure conditions similar to those observed in urban areas of the United States. METHODS: Using a double-blind, counter-balanced design, we exposed 9 (5 women and 4 men) subjects with mild atopic asthma (house dust mite sensitive) to clean air and to 0.16 ppm ozone for 7.6 hours; exposures were separated by a minimum of 4 weeks. During exposure, subjects performed light exercise (ventilation = 24 L/min) for 50 minutes of each hour, and pulmonary function was evaluated before and after exposures. The morning after exposure, subjects underwent bronchial challenge with inhaled house dust mite allergen (Dermatophagoides farinae). Using a series of doubling allergen concentrations, subjects inhaled 5 breaths of nebulized allergen (0.06 to 500 AU/mL) at 10-minute intervals until a minimum of a 20% decrement in FEV(1) was elicited. RESULTS: Compared with the change in FEV(1) during air exposure, there was a mean 9.1% +/- 2.5% (SEM) decrement in FEV(1) observed because of ozone (P <.01). Seven of the 9 subjects required less allergen after ozone exposure than after air exposure; there was a 0.58 mean dose shift in the doubling concentration of allergen attributable to the ozone exposure (P =.03). CONCLUSION: These findings indicate that exposure of subjects with mild atopic asthma to ozone at levels sufficient to cause modest decrements in lung function also increases the reactivity to allergen. To the extent that this effect occurs in response to ambient exposures, ozone may be contributing to the aggravation of asthma.

Adult↗
PubMed1999

Eosinophil influx to the nasal airway after local, low-level LPS challenge in humans.

BACKGROUND: Recent observations show that atopic asthmatic subjects have increased sensitivity to respirable endotoxin (or LPS) compared with normal persons. In vitro studies demonstrate that LPS enhances eosinophil survival. These observations suggest that the effects of inhaled LPS in asthmatic subjects may include increases in the number of airway eosinophils. OBJECTIVE: We sought to determine whether low-level nasal LPS challenge causes an increase in eosinophil numbers in the nasal airways of atopic or normal subjects. METHODS: Sixteen volunteers (10 atopic asthmatic subjects and 6 normal subjects) underwent 2 nasal challenge sessions. In one session, one nostril was challenged with saline and the other with 0. 1 microg of LPS. During the second session, 0.3 microg and 1.0 microg of LPS was delivered to each nostril, respectively. Nasal lavage fluid was obtained from each nostril before challenge, as well as 4 and 24 hours after challenge, and examined for the percent of total cells that were eosinophils and neutrophils, as well as cytokine levels. RESULTS: LPS (1.0 microg) increased the percent of eosinophils in nasal lavage fluid 4 hours after challenge in atopic subjects only. There was also a correlation between constitutive nasal GM-CSF and eosinophil response to LPS in atopic subjects. CONCLUSION: LPS challenge increases eosinophils in the airways of atopic subjects.

Adolescent↗
PubMed1999

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.

Adolescent↗
PubMed1998

Inhaled fluticasone propionate delivered by means of two different multidose powder inhalers is effective and safe in a large pediatric population with persistent asthma.

BACKGROUND: Inhaled corticosteroids are increasingly being used to treat mild-to-moderate asthma in children. However, data regarding therapy with this class of compounds, especially in children under age 6 years, is limited. Fluticasone propionate is a third generation inhaled corticosteroid with an optimal therapeutic index. Few large prospective clinical trials have been conducted to evaluate the efficacy and safety of fluticasone propionate powder in children. OBJECTIVE: We sought to determine the efficacy and safety of fluticasone propionate powder administered by means of the Diskus and Diskhaler multidose powder inhalers in pediatric patients with persistent asthma. METHODS: Fluticasone propionate powder (50 microg or 100 microg twice daily) or placebo was administered by means of the Diskus or Diskhaler inhalers to 437 children (4 to 11 years old) with persistent asthma for 12 weeks in a randomized, double-blind, parallel-group, multi-center trial. Patients were stratified according to whether they were receiving prior treatment with inhaled corticosteroids or cromolyn or beta2-agonists alone. RESULTS: Fluticasone propionate powder administered by means of Diskus or Diskhaler significantly improved FEV1 (mean increase from baseline of 0.22 to 0.24 L; p < or = 0.023), clinic morning peak expiratory flow (mean increase from baseline of 48 to 55 L/min; p < or = 0.006), patient-measured morning (p < or = 0.001) and evening (p < or = 0.003) peak expiratory flow, and asthma symptom scores (in all but the 50 microg Diskus group; p < or = 0.036), as well as reduced albuterol use (p < or = 0.002) and nighttime awakenings (p < or = 0.019) at endpoint. Efficacy parameters were not significantly different between the two doses with either device. More placebo-treated patients discontinued the study because of lack of efficacy than patients in any fluticasone propionate group (p < 0.001). Fluticasone propionate did not suppress morning plasma cortisol concentrations and did not affect 24-hour urinary free-cortisol excretion. Adverse events were primarily pharmacologic effects of inhaled corticosteroids, and those related to the study drug occurred with low frequency. Patient satisfaction with both the Diskus and Diskhaler devices was high, with a majority of patients (> 80%) rating them favorably. CONCLUSION: This study demonstrated that fluticasone propionate powder, at the conventional recommended doses of up to 200 microg/day administered by means of Diskus or Diskhaler, was well tolerated and improved lung function in children even as young as 4 and 5 years old regardless of whether they were previously treated with inhaled corticosteroids or cromolyn or beta2-agonists alone.

Administration, Inhalation↗
PubMed1997

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.

Asthma↗
PubMed1997

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.

Air Pollutants↗
PubMed1997

Epithelial cell-conditioned media inhibits degranulation of the RBL-2H3 rat mast cell line.

The effect of epithelial cells on mast cell responses was investigated by examination of degranulation of the rat mast cell line RBL-2H3 after overnight culture in media conditioned by the BEAS-2B human bronchial epithelial cell line [epithelial cell-conditioned media (ECM)]. These studies indicate that BEAS-2B cells secrete an inhibitor(s) of immunoglobulin E and A-23187-mediated degranulation of the RBL-2H3 cell line. The inhibitory activities of ECM are recovered after filtration through a 3-kDa cutoff filter. Pharmacological inhibition of cyclooxygenase in the BEAS-2B cells before preparation of ECM has no effect on subsequent inhibition of mast cell degranulation by ECM. However, cycloheximide treatment of the BEAS-2B cells before the conditioning process does preclude development of mast cell inhibitor activity in ECM, suggesting that this activity depends on protein synthesis. The effects of ECM on mast cell function are reversible, demonstrating that these effects do not result from overt cytotoxicity. Finally, media conditioned by primary cultures of human respiratory epithelial cells, but not fibroblasts, influence RBL-2H3 degranulation in a manner similar to ECM, suggesting that secretion of mast cell inhibitors may be somewhat unique to epithelial cells.

Animals↗
PubMed1996

Allergen bronchoprovocation of patients with mild allergic asthma after ozone exposure.

BACKGROUND: Clinical and epidemiologic studies suggest that ambient ozone exposure may increase the response of patients with asthma to inhaled allergen. OBJECTIVES: The study was designed to evaluate whether a resting 1-hour exposure to 0.12 ppm ozone increases the sensitivity of patients with atopic asthma to inhaled allergen. METHODS: Outside of their allergen season, 15 patients with mild atopic asthma (5 women and 10 men) were exposed, on separate occasions, for 1 hour at rest to clean air and 0.12 ppm ozone. Exposures were separated by a minimum of 4 weeks in a counterbalanced, double-blind design. After exposure, subjects underwent inhalation challenge with doubling doses of aerosolized allergen (0.05 to a maximum of 1600 protein nitrogen units/ml) until we elicited a 20% FEV1 decrement (PC20). RESULTS: Baseline symptoms, spirometry, and histamine bronchoreactivity were similar for the two exposures. Neither spirometry results nor symptoms were significantly changed after either exposure. The mean difference in response to allergen challenge on the air and ozone days, for the 12 subjects who attained a PC20 was not significant (p = 0.124). Three subjects required the same allergen dose to reach PC20 for both exposures, five required less allergen after ozone exposure, and four required more. There was no order effect for the acute response to allergen challenges (p = 0.325). However, 20 hours after allergen challenge, histamine bronchoreactivity was increased (p < 0.05) to a similar degree for both air and ozone. CONCLUSIONS: A resting exposure for 1 hour to 0.12 ppm ozone did not potentiate an immediate bronchoconstrictive response to grass allergen in this group of patients with mild atopic asthma.

Administration, Inhalation↗
PubMed1996

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.

Air Pollutants↗