Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice
ABSTRACT Ozone is a common urban environmental air pollutant and significantly contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced bronchoconstriction, remain poorly understood. Hyaluronan was recently shown to play a central role in the response to noninfectious lung injury. Therefore, we hypothesized that hyaluronan contributes to airway hyperreactivity (AHR) after exposure to ambient ozone. Using an established model of ozone-induced airways disease, we characterized the role of hyaluronan in airway hyperresponsiveness. The role of hyaluronan in response to ozone was determined by using therapeutic blockade, genetically modified animals, and direct challenge to hyaluronan. Ozone-exposed mice demonstrate enhanced AHR associated with elevated hyaluronan levels in the lavage fluid. Mice deficient in either CD44 (the major receptor for hyaluronan) or inter-alpha-trypsin inhibitor (molecule that facilitates hyaluronan binding) show similar elevations in hyaluronan but are protected from ozone-induced AHR. Mice pretreated with hyaluronan-binding peptide are protected from the development of ozone-induced AHR. Overexpression of hyaluronan enhances the airway response to ozone. Intratracheal instillation of endotoxin-free low molecular weight hyaluronan induces AHR dependent on CD44, whereas instillation of high molecular weight hyaluronan protects against ozone-induced AHR. In conclusion, we demonstrate that hyaluronan mediates ozone-induced AHR, which is dependent on the fragment size and both CD44 and inter-alpha-trypsin inhibitor. These data support the conclusion that pulmonary matrix can contribute to the development of airway hyperresponsiveness.
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ABSTRACT: Background: Epidemiologic and experimental studies have reported a variety of health effects in response to ozone (O-3) exposure, and some have indicated that certain populations may be at increased or decreased risk of O-3-related health effects. Objectives: We sought to identify potential response-modifying factors to determine whether specific groups of the population or life stages are at increased or decreased risk of O-3-related health effects using a weight-of-evidence approach. Methods: Epidemiologic, experimental, and exposure science studies of potential factors that may modify the relationship between O3 and health effects were identified in U. S. Environmental Protection Agency's 2013 Integrated Science Assessment for Ozone and Related Photochemical Oxidants. Scientific evidence from studies that examined factors that may influence risk were integrated across disciplines to evaluate consistency, coherence, and biological plausibility of effects. The factors identified were then classified using a weight-of-evidence approach to conclude whether a specific factor modified the response of a population or life stage, resulting in an increased or decreased risk of O-3-related health effects. Discussion: We found "adequate" evidence that populations with certain genotypes, preexisting asthma, or reduced intake of certain nutrients, as well as different life stages or outdoor workers, are at increased risk of O-3-related health effects. In addition, we identified other factors (i.e., sex, socioeconomic status, and obesity) for which there was "suggestive" evidence that they may increase the risk of O-3-related health effects. Conclusions: Using a weight-of-evidence approach, we identified a diverse group of factors that should be considered when characterizing the overall risk of health effects associated with exposures to ambient O-3.Environmental Health Perspectives 06/2014; 122(11). DOI:10.1289/ehp.1307541 · 7.03 Impact Factor
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ABSTRACT: Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24-72 h), neutrophilic inflammation and IL-6 are augmented in adiponectin deficient (Adipo(-/-)) mice. The IL-17/G-CSF axis is required for this increased neutrophilia. We hypothesized that elevated IL-6 in Adipo(-/-) mice contributes to their augmented responses to ozone via effects on IL-17A expression. Therefore, we generated mice deficient in both adiponectin and IL-6 (Adipo(-/-)IL-6(-/-)) and exposed them to ozone or air. In ozone exposed mice, BAL neutrophils, IL-6, and G-CSF, and pulmonary Il17α mRNA expression were greater in Adipo(-/-) versus wildtype mice, but reduced in Adipo(-/-)IL-6(-/-) versus Adipo(-/-) mice. IL-17A+ F4/80+ cells and IL-17A(+) γδ T-cells were also reduced in Adipo(-/-)IL-6(-/-) versus Adipo(-/-) mice exposed to ozone. Only BAL neutrophils were reduced in IL-6(-/-) versus WT mice. In wildtype mice, IL-6 was expressed in Gr-1(+)F4/80(-)CD11c(-) cells, whereas in Adipo-/- mice, F4/80(+)CD11c(+) cells also expressed IL-6, suggesting that IL-6 is regulated by adiponectin in these alveolar macrophages. Transcriptomic analysis identified serum amyloid A3 (Saa3), which promotes IL-17A expression, as the gene most differentially augmented by ozone in Adipo(-/-) versus wildtype mice. After ozone, Saa3 mRNA expression was markedly greater in Adipo(-/-) versus wildtype mice, but reduced in Adipo(-/-)/IL-6(-/-) versus Adipo(-/-) mice. In conclusion, our data support a pivotal role of IL-6 in the hyperinflammatory condition observed in Adipo(-/-) mice after ozone exposure, and suggest that this role of IL-6 involves its ability to induce Saa3, IL-17A and G-CSF.AJP Lung Cellular and Molecular Physiology 12/2013; 306(6). DOI:10.1152/ajplung.00235.2013 · 4.04 Impact Factor
Frontiers in Bioscience 01/2013; 18(3):838. DOI:10.2741/4147 · 4.25 Impact Factor