Katherine Mills

Estimating error in using ambient PM2.5 concentrations as proxies for personal exposures: A review

Background: Several methods have been used to account for measurement error inherent in using ambient concentration of particulate matter <2.5 &mgr;m/m3 (PM2.5) as a proxy for personal exposure. Such methods commonly rely on the estimated correlation between ambient and personal PM2.5 concentrations (r). However, studies of r have not been systematically and quantitatively assessed for publication bias or heterogeneity. Methods: We searched 7 electronic reference databases for studies of the within-participant correlation between ambient and personal PM2.5. Results: We identified 567 candidate studies, 18 (3%) of which met inclusion criteria and were abstracted. The studies were published between 1999 and 2008, representing 619 nonsmoking participants aged 6–93 years in 17 European and North American cities. Correlation coefficients (median 0.54; range 0.09–0.83) were based on a median of 8 ambient-personal PM2.5 pairs per participant (range 5–20) collected over 27–547 days. Overall, there was little evidence for publication bias (funnel plot symmetry tests: Beggs log-rank test, P = 0.9; Eggers regression asymmetry test, P = 0.2). However, strong evidence for heterogeneity was noted (Cochrans Q test for heterogeneity, P < 0.001). European locales, eastern longitudes in North America, higher ambient PM2.5 concentrations, higher relative humidity, and lower between-participant variation in r were associated with increased r. Conclusions: Characteristics of participants, studies, and the environments in which they are conducted may affect the accuracy of ambient PM2.5 as a proxy for personal exposure.

Vitamin E, γ-tocopherol, reduces airway neutrophil recruitment after inhaled endotoxin challenge in rats and in healthy volunteers.

Epidemiologic studies suggest that dietary vitamin E is an important candidate intervention for asthma. Our group has shown that daily consumption of vitamin E (γ-tocopherol, γT) has anti-inflammatory actions in both rodent and human phase I studies. The objective of this study was to test whether γT supplementation could mitigate a model of neutrophilic airway inflammation in rats and in healthy human volunteers. F344/N rats were randomized to oral gavage with γT versus placebo, followed by intranasal LPS (20μg) challenge. Bronchoalveolar lavage fluid and lung histology were used to assess airway neutrophil recruitment. In a phase IIa clinical study, 13 nonasthmatic subjects completed a double-blinded, placebo-controlled crossover study in which they consumed either a γT-enriched capsule or a sunflower oil placebo capsule. After 7 days of daily supplementation, they underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 6 h after inhaled LPS. The effect of γT compared to placebo on airway neutrophils post-LPS was compared using a repeated-measures analysis of variance. In rats, oral γT supplementation significantly reduced tissue infiltration (p<0.05) and accumulation of airway neutrophils (p<0.05) that are elicited by intranasal LPS challenge compared to control rats. In human volunteers, γT treatment significantly decreased induced sputum neutrophils (p=0.03) compared to placebo. Oral supplementation with γT reduced airway neutrophil recruitment in both rat and human models of inhaled LPS challenge. These results suggest that γT is a potential therapeutic candidate for prevention or treatment of neutrophilic airway inflammation in diseased populations.

IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers.

BACKGROUND Asthma with neutrophil predominance is challenging to treat with corticosteroids. Novel treatment options for asthma include those that target innate immune activity. Recent literature has indicated a significant role for IL-1β in both acute and chronic neutrophilic asthma. OBJECTIVE This study used inhaled endotoxin (LPS) challenge as a model of innate immune activation to (1) assess the safety of the IL-1 receptor antagonist anakinra in conjunction with inhaled LPS and (2) to test the hypothesis that IL-1 blockade will suppress the acute neutrophil response to challenge with inhaled LPS. METHODS In a phase I clinical study 17 healthy volunteers completed a double-blind, placebo-controlled crossover study in which they received 2 daily subcutaneous doses of 1 mg/kg anakinra (maximum dose, 100 mg) or saline (placebo). One hour after the second treatment dose, subjects underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 4 hours after inhaled LPS. The effect of anakinra compared with placebo on airway neutrophil counts and airway proinflammatory cytokine levels after LPS challenge was compared by using a linear mixed-model approach. RESULTS Anakinra pretreatment significantly diminished airway neutrophilia compared with placebo. LPS-induced IL-1β, IL-6, and IL-8 levels were significantly reduced during the anakinra treatment period compared with those seen after placebo. Subjects tolerated the anakinra treatment well without an increased frequency of infections attributable to anakinra treatment. CONCLUSIONS Anakinra effectively reduced airway neutrophilic inflammation and resulted in no serious adverse events in a model of inhaled LPS challenge. Anakinra is a potential therapeutic candidate for treatment of asthma with neutrophil predominance in diseased populations.

Estimating Error in Using Residential Outdoor PM2.5 Concentrations as Proxies for Personal Exposures: A Meta-analysis

Background Studies examining the health effects of particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5) commonly use ambient PM2.5 concentrations measured at distal monitoring sites as proxies for personal exposure and assume spatial homogeneity of ambient PM2.5. An alternative proxy—the residential outdoor PM2.5 concentration measured adjacent to participant homes—has few advantages under this assumption. Objectives We systematically reviewed the correlation between residential outdoor PM2.5 and personal PM2.5 (r̄j) as a means of comparing the magnitude and sources of measurement error associated with their use as exposure surrogates. Methods We searched seven electronic reference databases for studies of the within-participant residential outdoor-personal PM2.5 correlation. Results The search identified 567 candidate studies, nine of which were abstracted in duplicate, that were published between 1996 and 2008. They represented 329 nonsmoking participants 6–93 years of age in eight U.S. cities, among whom r̄j was estimated (median, 0.53; range, 0.25–0.79) based on a median of seven residential outdoor-personal PM2.5 pairs per participant. We found modest evidence of publication bias (symmetric funnel plot; pBegg = 0.4; pEgger = 0.2); however, we identified evidence of heterogeneity (Cochran’s Q-test p = 0.05). Of the 20 characteristics examined, earlier study midpoints, eastern longitudes, older mean age, higher outdoor temperatures, and lower personal-residential outdoor PM2.5 differences were associated with increased within-participant residential outdoor-personal PM2.5 correlations. Conclusions These findings were similar to those from a contemporaneous meta-analysis that examined ambient-personal PM2.5 correlations (r̄j = median, 0.54; range, 0.09–0.83). Collectively, the meta-analyses suggest that residential outdoor-personal and ambient-personal PM2.5 correlations merit greater consideration when evaluating the potential for bias in studies of PM2.5-mediated health effects.

Long-term association between self-reported signs and symptoms and heart failure hospitalizations: the Atherosclerosis Risk In Communities (ARIC) Study

Although studies of the accuracy of heart failure (HF) classification scoring systems are available, few have examined their performance when restricted to self‐reported items.

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.

Body mass index correlates with pollutant-induced interleukin-1β in sputum and blood

Increasing BMI has been proposed to be associated with asthma development and with airway hyperresponsiveness that is harder to treat with conventional therapies1,2. Increased BMI has been associated with ozone-induced decrements in spirometry3 in humans as well as with increased pulmonary inflammation following ozone (O3) exposure in murine models of obese mice.4,5 Murine studies have recently demonstrated that the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, responsible for release of mature IL-1β from a cell, played an important role in obesity-induced airway hyperresponsiveness through the induction of IL-17a-producing innate lymphoid cells type 3 (ILC3)6. Furthermore, IL-1β blockade was able to mitigate obesity-induced airway hyperreactivity6. Addition of the saturated fatty acid palmitate to in vitro cultures (macrophage) after LPS-priming was sufficient to induce IL-1β release through NLRP3 activation.7 These two studies add to a growing body of evidence that the NLRP3 inflammasome may represent a central figure in BMI-driven pulmonary inflammation and enhanced susceptibility to environmental stimuli. Previous work has shown that increased BMI influences O3-induced decrements in spirometry in otherwise healthy human volunteers3. However, studies examining the relationship between pollutant-induced pulmonary inflammation in overweight and obese humans are still lacking. We hypothesized that increased BMI would be associated with increased airway inflammation after an environmental challenge with O3.

Interleukin-13 stimulates production of nitric oxide in cultured human nasal epithelium

The diversity and extent of signaling functions of nitric oxide (NO) in cell physiology as well as its presence and influence as a common component of ambient air pollution and tobacco smoke are gaining increasing research attention relative to both health and disease. While cellular NO production is typically associated with inflammatory cells and processes, the airway epithelium particularly of the paranasal sinuses, has been documented to be a rich source of excreted NO. Inasmuch as excreted NO derives from both mucosal and inflammatory cell sources, distinguishing the individual contribution of these compartments to total excreted cellular NO is potentially problematic. We simulated an inflammatory mucosal environment by stimulating human nasal epithelial cultures with interleukin-13 (IL-13), a mediator produced by eosinophils in asthma, allergic rhinitis, and sinusitis. While a consistent baseline of NO excretion in control cultures was documented, widely variable individual responses to IL-13 exposure were observed in companion cultures maintained under identical conditions and tested at the same time. These studies suggest that cellular NO excretion by the healthy epithelial mucosa is subject to considerable individual variability and may be significantly elevated among some individuals in the presence of IL-13 stimulation.

Low-level ozone has both respiratory and systemic effects in African American adolescents with asthma despite asthma controller therapy

In a cohort of African American adolescents with persistent asthma on guidelines-based daily controller therapies, short-term elevation of low ozone levels below the National Ambient Air Quality Standard of 70 ppb were associated with lung function decrements and elevated lipid levels.