Genetic mechanisms of susceptibility to ozone-induced lung disease
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA. Annals of the New York Academy of Sciences
(Impact Factor: 4.38).
08/2010; 1203(1):113-9. DOI: 10.1111/j.1749-6632.2010.05606.x
Environmental oxidants remain a major public health concern in industrialized cities throughout the world. Population and epidemiological studies have associated oxidant air pollutants with morbidity and mortality outcomes, and underscore the important detrimental effects of these pollutants on the lung. Interindividual variation in pulmonary responses to air pollutants suggests that some subpopulations are at increased risk to detrimental effects of pollutant exposure, and it has become clear that genetic background is an important susceptibility factor. A number of genetics and genomics tools have recently emerged to enable identification of genes that contribute to differential responsiveness to oxidants, including ozone (O(3)). Integrative omics approaches have been applied in inbred mice to identify genes that determine differential responsiveness to O(3)-induced injury and inflammation, including Tnf, Tlr4, and MHC Class II genes. Combined investigations across cell models, inbred mice, and humans have provided, and will continue to provide, important insight to understanding genetic factors that contribute to differential susceptibility to oxidants.
Available from: Leopoldo Aguilera-Aguirre
- "Multiple interacting risk factors such as allergens, environmental tobacco smoke, particulate matter, oxides of nitrogen, ozone, and repeated respiratory virus exposures that induce and/or augment reactive oxygen species (ROS) in the airways have been identified [6-8]. Cellular oxidative stress induced by ROS plays a fundamental role in inflammation through the activation of inflammatory signals which activate stress kinases such as ERK1/2, p38 and JNK, which in turn activate redox-sensitive transcription factors such as NF-κB that transcribe pro-inflammatory genes [9-12]. "
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ABSTRACT: Childhood hospitalization related to asthma remains at historically high levels, and its incidence is on the rise world-wide. Previously, we have demonstrated that aldose reductase (AR), a regulatory enzyme of polyol pathway, is a major mediator of allergen-induced asthma pathogenesis in mouse models. Here, using AR null (AR-/-) mice we have investigated the effect of AR deficiency on the pathogenesis of ragweed pollen extract (RWE)-induced allergic asthma in mice and also examined the efficacy of enteral administration of highly specific AR inhibitor, fidarestat.
The wild type (WT) and AR-/- mice were sensitized and challenged with RWE to induce allergic asthma. AR inhibitor, fidarestat was administered orally. Airway hyper-responsiveness was measured in unrestrained animals using whole body plethysmography. Mucin levels and Th2 cytokine in broncho-alveolar lavage (BAL) were determined using mouse anti-Muc5A/C ELISA kit and multiplex cytokine array, respectively. Eosinophils infiltration and goblet cells were assessed by H&E and periodic acid Schiff (PAS)-staining of formalin-fixed, paraffin-embedded lung sections. T regulatory cells were assessed in spleen derived CD4+CD25+ T cells population.
Deficiency of AR in mice led to significantly decreased PENH, a marker of airway hyper-responsiveness, metaplasia of airway epithelial cells and mucus hyper-secretion following RWE-challenge. This was accompanied by a dramatic decrease in infiltration of eosinophils into sub-epithelium of lung as well as in BAL and release of Th2 cytokines in response to RWE-challenge of AR-/- mice. Further, enteral administration of fidarestat significantly prevented eosinophils infiltration, airway hyper-responsiveness and also markedly increased population of T regulatory (CD4+CD25+FoxP3+) cells as compared to RWE-sensitized and challenged mice not treated with fidarestat.
Our results using AR-/- mice strongly suggest the role of AR in allergic asthma pathogenesis and effectiveness of oral administration of AR inhibitor in RWE-induced asthma in mice supports the use of AR inhibitors in the treatment of allergic asthma.
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ABSTRACT: Exposure to environmental chemicals and other environmental stressors have health impacts on the fetus that may not be apparent until later in life. The concept of developmental origins of disease should be expanded to include these early life exposures in addition to the effects of nutrition and maternal factors. This paper will describe the toxicological, biological and epidemiological issues that are pertinent to conducting research on environmental exposures early in life and their health consequences over the life span.
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ABSTRACT: The purpose of this review is to provide an update of the current understanding on the role of microRNAs in mediating genetic responses to air pollutants and to contemplate on how these responses ultimately control susceptibility to ambient air pollution. Morbidity and mortality attributable to air pollution continues to be a growing public health concern worldwide. Despite several studies on the health effects of ambient air pollution, underlying molecular mechanisms of susceptibility and disease remain elusive. In the last several years, special attention has been given to the role of epigenetics in mediating, not only genetic and physiological responses to certain environmental insults, but also in regulating underlying susceptibility to environmental stressors. Epigenetic mechanisms control the expression of gene products, both basally and as a response to a perturbation, without affecting the sequence of DNA itself. These mechanisms include structural regulation of the chromatin structure, such as DNA methylation and histone modifications, and post-transcriptional gene regulation, such as microRNA mediated repression of gene expression. microRNAs are small noncoding RNAs that have been quickly established as key regulators of gene expression. As such, miRNAs have been found to control several cellular processes including apoptosis, proliferation and differentiation. More recently, research has emerged suggesting that changes in the expression of some miRNAs may be critical for mediating biological, and ultimately physiological, responses to air pollutants. Although the study of microRNAs, and epigenetics as a whole, has come quite far in the field of cancer, the understanding of how these mechanisms regulate gene-environment interactions to environmental exposures in everyday life is unclear. This article does not necessarily reflect the views and policies of the US EPA.
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