Methylation of cysteinyl leukotriene receptor 1 genes associates with lung function in asthmatics exposed to traffic-related air pollution.

Air pollution is associated with early declines in lung function and increased levels of asthma-related cysteinyl leukotrienes (CysLT) but a biological pathway linking this rapid response has not been delineated. In this randomized controlled diesel exhaust (DE) challenge study of 16 adult asthmatics, increased exposure-attributable urinary leukotriene E4 (uLTE4, a biomarker of cysteinyl leukotriene production) was correlated (p = 0.04) with declines in forced expiratory volume in 1-second (FEV1) within 6 hours of exposure. Exposure-attributable uLTE4 increases were correlated (p = 0.02) with increased CysLT receptor 1 (CysLTR1) methylation in peripheral blood mononuclear cells which, in turn, was marginally correlated (p = 0.06) with decreased CysLTR1 expression. Decreased CysLTR1 expression was, in turn, correlated (p = 0.0007) with FEV1 declines. During the same time period, increased methylation of GPR17 (a negative regulator of CysLTR1) was observed after DE exposure (p = 0.02); this methylation increase was correlated (p = 0.001) with decreased CysLTR1 methylation which, in turn, was marginally correlated (p = 0.06) with increased CysLTR1 expression; increased CysLTR1 expression was correlated (p = 0.0007) with FEV1 increases. Collectively, these data delineate a potential mechanistic pathway linking increased DE exposure-attributable CysLT levels to lung function declines through changes in CysLTR1-related methylation and gene expression.

Health effects of concurrent ambient and tobacco smoke-derived particle exposures at low concentrations in children with asthma.

Exposure to particulate matter less than 2.5 microns from either ambient pollution (AMB-PM2.5) or secondhand smoke (SHS-PM2.5) have been associated with asthma worsening, but there is little information on effects and relative potency with concurrent exposures. We studied health effects of concurrent exposures to AMB-PM2.5 and SHS-PM2.5 over a 6-year period in schoolchildren with asthma. Regression calibration with instrumental variables (RCIV) was utilized to estimate effects of personal exposure to low-level SHS and AMB-PM2.5 on daily albuterol usage and urinary leukotriene E4 (uLTE4; a biomarker of asthma-related inflammation) using urine cotinine and concentrations from fixed and personal pollution monitors. Each IQR increase in SHS-PM2.5 exposure was associated with a 6.7% increase (95% CI: 1.0-12.8%) in uLTE4 on the same day and 9.4% increase (95% CI: -2.6 to 22.7%) in albuterol use the next day, when children were co-exposed to mean levels of AMB-PM2.5. The dose-response relationship between health outcomes and one pollutant was higher at lower levels of the other pollutant. For example, at lower levels of predicted SHS-PM2.5 exposure, increases in health outcomes per IQR increase in AMB-PM2.5 ranged between 2 and 5%, but were negligible at higher SHS-PM2.5 levels. Comparing at equivalent co-exposure levels, SHS-PM2.5 was 1.6 times more potent than AMB-PM2.5 for uLTE4 (95% CI: 1.1-2.3); estimates for albuterol usage were similar but less significant. Effects at mean co-exposure levels were closer [SHS to AMB-PM2.5 potency ratio = 1.2 (95% CI: 0.9-1.5) for uLTE4 and 1.2 (95% CI: 0.7-1.9) for albuterol usage]. In summary, concurrent exposure to relatively low levels of SHS and AMB-PM2.5 were associated with health outcomes in asthmatic schoolchildren. Dose responses varied with changes in the relative amounts of each pollutant; SHS-PM2.5 was observed to be more potent than AMB-PM2.5 when co-exposure levels were equivalent.

Urinary Leukotriene E4 as a Biomarker of Exposure, Susceptibility, and Risk in Asthma: An Update.

Measurement of urinary leukotriene E4 (uLTE4) is a sensitive and noninvasive method of assaying total body cysteinyl leukotriene (CysLT) production and changes in CysLT production. Recent studies have reported on novel LTE4 receptor interactions and genetic polymorphisms causing CysLT variability. The applications of uLTE4 as a biomarker continue to expand, including evaluation of environmental exposures, asthma severity risk, aspirin sensitivity, predicting atopy in preschool age children, obstructive sleep apnea, and predicting susceptibility to leukotriene receptor antagonists.

Within-microenvironment exposure to particulate matter and health effects in children with asthma: a pilot study utilizing real-time personal monitoring with GPS interface.

BACKGROUND: Most particulate matter (PM) and health studies in children with asthma use exposures averaged over the course of a day and do not take into account spatial/temporal variability that presumably occurs as children move from home, into transit and then school microenvironments. The objectives of this work were to identify increases in morning PM exposure occurring within home, transit and school microenvironments and determine their associations with asthma-related inflammation and rescue medication use. METHODS: In 2007-2008, thirty Denver-area schoolchildren with asthma performed personal PM exposure monitoring using a real-time sensor integrated with a geographic information system (GIS) to apportion exposures to home, transit and school microenvironments. Concurrently, daily monitoring of the airway inflammatory biomarker urinary leukotriene E4 (uLTE4) and albuterol usage was performed. RESULTS: Mean PM exposures each morning were relatively well correlated between microenvironments for subject samples (0.3 < r < 0.8), thus limiting use of this exposure metric to attribute health effects to PM exposure in specific microenvironments. Within-microenvironment increases in exposure, such as would be characterized by one or a series of transient spikes or a sustained increase in concentration (exposure event), however, were not strongly correlated between microenvironments (|r| < 0.25). On days when children were exposed to a ≥ 5µg/m3 exposure event during transit, they demonstrated a 24.0 % increase in uLTE4 (95 % CI: 1.5 %, 51.5 %) and a 9.7 % (-5.9 %, 27.9 %) increase in albuterol usage compared to days without transit exposure events. Associations between exposure events and health outcomes in home and school microenvironments tended to be positive as well, but weaker than for transit. CONCLUSIONS: School children with asthma moving across morning microenvironments experience spatially heterogeneous PM exposures with potentially varying health effects.

Predictors of asthma control and lung function responsiveness to step 3 therapy in children with uncontrolled asthma.

BACKGROUND: Predictors of improvement in asthma control and lung function to step 3 therapy in children with persistent asthma have not been identified despite reported heterogeneity in responsiveness. OBJECTIVE: We sought to evaluate potential predictors of asthma control and lung function responsiveness to step 3 therapy. METHODS: A post hoc analysis from the Best Add-On Giving Effective Response (BADGER) study tested the association between baseline biological, asthma control, pulmonary function, and demographic markers and responsiveness to step-up to a higher dose of inhaled corticosteroid (ICS step-up therapy) or addition of leukotriene receptor antagonist (LTRA step-up therapy) or long-acting ß2-agonist (LABA step-up therapy). RESULTS: In multivariate analyses higher impulse oscillometry reactance area was associated (P = .048) with a differential FEV1 response favoring LABA over ICS step-up therapy, whereas higher urinary leukotriene E4 levels were marginally (P = .053) related to a differential FEV1 response favoring LTRA over LABA step-up therapy. Predictors of differential responses comparing ICS with LTRA step-up therapy were not apparent, probably because of suppression of allergic markers with low-dose ICS treatment. Minimal overlap was seen across FEV1 and asthma control day predictors, suggesting distinct mechanisms related to lung function and asthma control day responses. CONCLUSION: Levels of impulse oscillometry reactance area indicating peripheral airway obstruction and urinary leukotriene E4 levels indicating cysteinyl leukotriene inflammation can differentiate LABA step-up responses from responses to LTRA or ICS step-up therapy. Further studies with physiologic, genetic, and biological markers related to these phenotypes will be needed to predict individual responses to LABA step-up therapy.

Regression calibration for models with two predictor variables measured with error and their interaction, using instrumental variables and longitudinal data.

Regression calibration provides a way to obtain unbiased estimators of fixed effects in regression models when one or more predictors are measured with error. Recent development of measurement error methods has focused on models that include interaction terms between measured-with-error predictors, and separately, methods for estimation in models that account for correlated data. In this work, we derive explicit and novel forms of regression calibration estimators and associated asymptotic variances for longitudinal models that include interaction terms, when data from instrumental and unbiased surrogate variables are available but not the actual predictors of interest. The longitudinal data are fit using linear mixed models that contain random intercepts and account for serial correlation and unequally spaced observations. The motivating application involves a longitudinal study of exposure to two pollutants (predictors) - outdoor fine particulate matter and cigarette smoke - and their association in interactive form with levels of a biomarker of inflammation, leukotriene E4 (LTE 4 , outcome) in asthmatic children. Because the exposure concentrations could not be directly observed, we used measurements from a fixed outdoor monitor and urinary cotinine concentrations as instrumental variables, and we used concentrations of fine ambient particulate matter and cigarette smoke measured with error by personal monitors as unbiased surrogate variables. We applied the derived regression calibration methods to estimate coefficients of the unobserved predictors and their interaction, allowing for direct comparison of toxicity of the different pollutants. We used simulations to verify accuracy of inferential methods based on asymptotic theory.

Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children.

RATIONALE: The effect of endotoxin on asthma morbidity in urban populations is unclear. OBJECTIVES: To determine if indoor pollutant exposure modifies the relationships between indoor airborne endotoxin and asthma health and morbidity. METHODS: One hundred forty-six children and adolescents with persistent asthma underwent repeated clinical assessments at 0, 3, 6, 9, and 12 months. Home visits were conducted at the same time points for assessment of airborne nicotine, endotoxin, and nitrogen dioxide (NO2) concentrations. The effect of concomitant pollutant exposure on relationships between endotoxin and asthma outcomes were examined in stratified analyses and statistical models with interaction terms. MEASUREMENTS AND MAIN RESULTS: Both air nicotine and NO2 concentrations modified the relationships between airborne endotoxin and asthma outcomes. Among children living in homes with no detectable air nicotine, higher endotoxin was inversely associated with acute visits and oral corticosteroid bursts, whereas among those in homes with detectable air nicotine, endotoxin was positively associated with these outcomes (interaction P value = 0.004 and 0.07, respectively). Among children living in homes with lower NO2 concentrations (<20 ppb), higher endotoxin was positively associated with acute visits, whereas among those living in homes with higher NO2 concentrations, endotoxin was negatively associated with acute visit (interaction P value = 0.05). NO2 also modified the effect of endotoxin on asthma symptom outcomes in a similar manner. CONCLUSIONS: The effects of household airborne endotoxin exposure on asthma are modified by coexposure to air nicotine and NO2, and these pollutants have opposite effects on the relationships between endotoxin and asthma-related outcomes.

Urinary leukotriene E4 as a biomarker of exposure, susceptibility and risk in asthma.

Measurement of urinary leukotriene E(4) (uLTE(4)) is a sensitive and noninvasive method of assaying total body cysteinyl leukotriene production and changes in cysteinyl leukotriene production. Recent studies have reported on novel uLTE(4) receptor interactions, and new applications for uLTE(4), as a biomarker of environmental exposure to tobacco smoke and ambient air pollution, a predictor of risk for asthma exacerbations related to tobacco smoke, and a marker of susceptibility to leukotriene receptor antagonists.