Air Pollution and Diet: Potential Interacting Exposures in Asthma.

PURPOSE OF REVIEW: To provide a review of emerging literature describing the impact of diet on the respiratory response to air pollution in asthma. RECENT FINDINGS: Asthma phenotyping (observable characteristics) and endotyping (mechanistic pathways) have increased the specificity of diagnostic and treatment pathways and opened the doors to the identification of subphenotypes with enhanced susceptibility to exposures and interventions. Mechanisms underlying the airway immune response to air pollution are still being defined but include oxidative stress, inflammation, and activation of adaptive and innate immune responses, with genetic susceptibility highlighted. Of these, neutrophil recruitment and activation appear prominent; however, understanding neutrophil function in response to pollutant exposures is a research gap. Diet may play a role in asthma pathogenesis and morbidity; therefore, diet modification is a potential target opportunity to protect against pollutant-induced lung injury. In particular, in vivo and in vitro data suggest the potential for diet to modify the inflammatory response in the airways, including impacts on neutrophil recruitment and function. Murine models provide compelling results in regard to the potential for dietary components (including fiber, antioxidants, and omega-3 fatty acids) to buffer against the inflammatory response to air pollution in the lung. Precision lifestyle approaches to asthma management and respiratory protection in the context of air pollution exposures may evolve to include diet, pending the results of further epidemiologic and causal investigation and with neutrophil recruitment and activation as a candidate mechanism.

Effects of ex vivo γ-tocopherol on airway macrophage function in healthy and mild allergic asthmatics.

Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate γ-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from nonsmoking healthy (n = 6) and mild house dust mite-sensitive allergic asthmatics (n = 6) were treated ex vivo with GT (300 µM) or saline (control). Phagocytosis of opsonized zymosan A bioparticles (Saccharomyces cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (p < 0.05) internalization of attached zymosan bioparticles and decreased (p < 0.05) macrophage expression of CD206, CD36 and CD86 in allergic asthmatics but not in controls. Overall, GT caused downregulation of both innate and adaptive immune response elements, and atopic status appears to be an important factor.

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.

Combination treatment with high-dose vitamin C and alpha-tocopherol does not enhance respiratory-tract lining fluid vitamin C levels in asthmatics.

Oxidative stress plays a significant role in allergic airway inflammation. Supplementation with alpha-tocopherol (alone or combined with ascorbate/vitamin C) has been assessed as an intervention for allergic airway diseases with conflicting results. Enhancing levels of airway antioxidants with oral supplements has been suggested as an intervention to protect individuals from the effect of inhaled oxidants, although it is unclear whether supplementation changes tocopherol or vitamin C levels in both serum and airway fluids. Our objective was to obtain pilot safety and dosing data from 14 allergic asthmatic volunteers examining the effect of daily combination oral therapy with 500 mg alpha-tocopherol (alpha T) and 2 g vitamin C for 12 wk. We examined serum and airway fluid and cellular levels of alpha- and gamma-tocopherol (gamma T) and vitamin C to plan for future studies of these agents in asthma and allergic rhinitis. Six volunteers completed 12 wk of active treatment with alpha T and vitamin C and 8 completed placebo. Blood and sputum samples were obtained at baseline and at 6 wk and 12 wk of therapy and were analyzed for alpha T, gamma T, and vitamin C levels in the serum, sputum supernatant, and sputum cells. Combination treatment increased serum vitamin C and significantly decreased sputum alpha T and serum gamma T levels. No changes were found in sputum supernatant or sputum cell vitamin C or serum alpha T levels in the active treatment group. In conclusion, supplementation with alpha T and high-dose vitamin C does not augment vitamin C levels in the respiratory-tract lining fluid.

Fluticasone propionate protects against ozone-induced airway inflammation and modified immune cell activation markers in healthy volunteers.

BACKGROUND: Ozone exposure induces airway neutrophilia and modifies innate immune monocytic cell-surface phenotypes in healthy individuals. High-dose inhaled corticosteroids can reduce O(3)-induced airway inflammation, but their effect on innate immune activation is unknown. OBJECTIVES: We used a human O(3) inhalation challenge model to examine the effectiveness of clinically relevant doses of inhaled corticosteroids on airway inflammation and markers of innate immune activation in healthy volunteers. METHODS: Seventeen O(3)-responsive subjects [>10% increase in the percentage of polymorphonuclear leukocytes (PMNs) in sputum, PMNs per milligram vs. baseline sputum] received placebo, or either a single therapeutic dose (0.5 mg) or a high dose (2 mg) of inhaled fluticasone proprionate (FP) 1 hr before a 3-hr O(3) challenge (0.25 ppm) on three separate occasions at least 2 weeks apart. Lung function, exhaled nitric oxide, sputum, and systemic biomarkers were assessed 1-5 hr after the O(3) challenge. To determine the effect of FP on cellular function, we assessed sputum cells from seven subjects by flow cytometry for cell-surface marker activation. RESULTS: FP had no effect on O(3)-induced lung function decline. Compared with placebo, 0.5 mg and 2 mg FP reduced O(3)-induced sputum neutrophilia by 18% and 35%, respectively. A similar effect was observed on the airway-specific serum biomarker Clara cell protein 16 (CCP16). Furthermore, FP pretreatment significantly reduced O(3)-induced modification of CD11b, mCD14, CD64, CD16, HLA-DR, and CD86 on sputum monocytes in a dose-dependent manner. CONCLUSIONS: This study confirmed and extended data demonstrating the protective effect of FP against O(3)-induced airway inflammation and immune cell activation.

In vivo gamma-tocopherol supplementation decreases systemic oxidative stress and cytokine responses of human monocytes in normal and asthmatic subjects.

We have recently reported that gamma-tocopherol (gammaT) reduces allergen- and zymosan-induced inflammation using rodent models. As an initial step in extending these observations to humans, we conducted an open-label, Phase I dosing study of two doses (one or two capsules daily for 1 week) of a gamma-tocopherol-rich preparation containing 623 mg of gamma-tocopherol, 61.1 mg of d-alpha-tocopherol, 11.1 mg of d-beta-tocopherol (11.1 mg), and 231 mg of d-sigma-tocopherol per capsule. Endpoints for this study include serum levels of 5-nitro-gamma-tocopherol, as a marker of oxidative stress, and changes in serum gamma-, alpha-, and delta-tocopherol and gamma-2'-carboxyethyl-6-hydroxychroman (CEHC) 6 and 24 h after the first dose and after 1 week of treatment. To assess the biological activity of this treatment, we obtained peripheral blood mononuclear cells at baseline and after 1 week of treatment with two capsules of a gamma-tocopherol-rich preparation/day and examined the inflammatory cytokine response of these cells in culture to ex vivo endotoxin/LPS (0.01 ng/ml) challenge. We also monitored a number of safety endpoints to examine how well this preparation is tolerated in eight normal volunteers (four allergic and four nonallergic) and eight allergic asthmatics. We further obtained human monocytes from a subset of these volunteers and treated them ex vivo with gammaT, alphaT, gamma-CEHC, and alpha-CEHC and assessed their actions on LPS-induced degradation of IkappaBalpha and JNK signaling and ROS generation. As detailed herein, this open-label study demonstrates that gamma-tocopherol-enriched supplementation decreased systemic oxidative stress, increased serum levels of gamma-tocopherol, and inhibited monocyte responses to LPS without any adverse health effects. Further, in vitro treatment of human monocytes with gamma-CEHC and alpha-CEHC inhibits ROS generation and LPS-induced degradation of IkappaB and JNK activation.