UTMB-CET: 2011 Pilot Projects
Role of SO₂ in Asthma Pathogenesis
PI: Bill Ameredes, Ph.D.; Co-PI: Edward Brooks, MD; Co-I: William Calhoun, MD
This project will investigate sulfur dioxide (SO₂) exposure in a mouse model of IL-10-deficient asthma, in order to determine how this important anti-inflammatory cytokine may be a key determinative agent behind the airway inflammation (AI) associated with an environmental pollutant. SO₂ continues to be a problem in a number of industrialized areas of the United States, and globally, in countries in which industrialization continues to develop, such as China. The rationale for this approach is based within two known aspects about asthma and pollution: 1) the fact that asthmatics have deficient IL-10 production, which may account for the reason that AI is poorly controlled in association with this disease, and 2) the fact that asthmatics have demonstrated exacerbations of AI in response to SO₂, as compared to non-asthmatics. Interestingly, no studies have been published investigating the role of IL-10 in SO₂-exacerbated AI; therefore, we base these studies in the utilization of an IL-10-deficient model of AI, in which mice inhale SO₂, mimicking the case of asthmatic SO₂ exposure. While some unrelated studies have suggested that the effect of SO₂ in asthma may be due to the production of reactive oxygen species within the airway, it is important to note that the there are no data regarding their association with IL-10, suggesting that the proposed study will be highly relevant and will provide critical preliminary data to support a subsequent R01 submission in this area. The project is constructed for 1 year of investigation using established models, executed by well-trained investigators, incorporating state-of-the-art high throughput methods of protein analyses, to maximize the possibility that this pilot will be successful. The Central Hypothesis is that IL-10 diminishes SO₂-exacerbated AI, through its anti-inflammatory modulation of cytokine and anti-oxidant pathways. However, it is the Corollary Hypothesis that is most important in relation to the effects of SO₂ in asthma, which is that lack of IL-10 increases SO₂-exacerbation of AI, through lack of downregulation of pro-inflammatory cytokine and reactive oxygen species (ROS) production. There are 2 specific aims of the project to test these possibilities, which will lead to a significantly better understanding of why SO₂ promotes exaggerated AI responses in asthma. Specific Aim 1 is to determine the lung cytokine and reactive oxygen species (ROS) profile of IL-10-deficient mice exposed to inhaled SO₂ in the setting of AI. Specific Aim 2 is to determine the cytokine and ROS release of human BAL leukocytes from non-asthmatics and asthmatics, exposed to SO₂ in vitro. The experiments will include investigations of IL-10 replacement in IL-10 deficient mice, and IL-10 neutralization in IL-10-sufficient strain-background-matched mice (C57Bl6), to determine the role of IL-10 in SO₂ responses. The BioPlex multi-cytokine assay will be used to rapidly identify IL-10 and SO₂ dependent alterations in the lung cytokine profile within the airway, airway cells in culture, and lung tissue. Colorimetric assays will be used to assay ROS in airway fluid, cells in culture, and tissue samples; Western assays will be utilized to identify anti-oxidant protein profile alterations, such as heme-oxygenase (HO-1) in the lung. This approach will allow us to comprehensively characterize the cytokine and anti-oxidant alterations, which will indicate how a lack of IL-10 influences the exaggerated AI response of the airways to SO₂. Because there is little to no data available in this area, these studies will provide novel and useful data regarding our understanding of the effects of SO₂ that can influence obstructive inflammatory lung diseases, such as asthma and COPD.
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