Obesity is an important public health problem that is a risk factor for cardiovascular disease, type II diabetes, some forms of cancer, and for asthma. Preliminary data indicates that the obese are also """"""""at risk"""""""" in terms of their susceptibility to air pollution, one of the triggers for asthma. The purpose of this proposal is to use animal models of obesity to examine the mechanistic basis for the relationship between obesity and asthma, using pulmonary responses to the air pollutant ozone (O3) as the outcome indicator. Preliminary data indicates obese mice have greater O3-induced airway inflammation and airway hyperresponsiveness than lean mice. Our hypothesis is that the increased systemic inflammation of obesity, particularly elevations in IL-6 and TNFa, prime lung cells to respond to inhaled pollutants with greater inflammatory responses and enhanced changes in lung function. Moreover, we hypothesize that this systemic inflammation is adipose tissue derived. Two types of obese mice will be employed, both on a C57BL/6 background: Cpefat mice and mice on high fat diets. Lean and obese mice will be exposed to filtered air or O3. After exposure, pulmonary mechanics and airway responsiveness to methacholine will be assessed, bronchoalveolar lavage (BAL) performed, and BAL markers of injury and inflammation measured. RNA will be prepared from the lungs and abdominal fat and analyzed for inflammatory gene mRNA expression by real time PCR. Serum will also be analyzed for markers of obese systemic inflammation.
In aim 1, we will determine whether obesity-related increases in responses to O3 correspond temporally with the expression of adipose tissue inflammatory genes, particularly IL-6 and TNFa, during the development of obesity.
In aim 2, we will ablate IL-6 and TNFa genetically or with antibodies, and increase systemic IL-6 and TNFa experimentally, to examine the role of IL-6 and TNFa in the effects of obesity on lung responses to O3.
In aim 3, we will examine the hypothesis that macrophages that infiltrate adipose tissue of obese mice are the source of the inflammatory molecules that augment airway responses to O3 in obesity. To do so, we will lethally irradiate mice to eradicate hematopoietic stem cells and then reconstitute them with fetal liver cells from genetically altered mice. Understanding the mechanistic basis for the augmented pulmonary responses to air pollution may lead to therapeutic strategies for reductions in responses to air pollution in this at risk population.
| Mathews, Joel A; Krishnamoorthy, Nandini; Kasahara, David I et al. (2018) Augmented Responses to Ozone in Obese Mice Require IL-17A and Gastrin-Releasing Peptide. Am J Respir Cell Mol Biol 58:341-351 |
| Cho, Youngji; Abu-Ali, Galeb; Tashiro, Hiroki et al. (2018) The Microbiome Regulates Pulmonary Responses to Ozone in Mice. Am J Respir Cell Mol Biol 59:346-354 |
| Mathews, Joel Andrew; Kasahara, David Itiro; Cho, Youngji et al. (2017) Effect of acute ozone exposure on the lung metabolomes of obese and lean mice. PLoS One 12:e0181017 |
| Mathews, Joel A; Krishnamoorthy, Nandini; Kasahara, David Itiro et al. (2017) IL-33 Drives Augmented Responses to Ozone in Obese Mice. Environ Health Perspect 125:246-253 |
| Shore, Stephanie A (2017) Mechanistic Basis for Obesity-related Increases in Ozone-induced Airway Hyperresponsiveness in Mice. Ann Am Thorac Soc 14:S357-S362 |
| Kasahara, D I; Mathews, J A; Ninin, F M C et al. (2017) Role of ROCK2 in CD4+ cells in allergic airways responses in mice. Clin Exp Allergy 47:224-235 |
| Brand, Jeffrey D; Mathews, Joel A; Kasahara, David I et al. (2016) Regulation of IL-17A expression in mice following subacute ozone exposure. J Immunotoxicol 13:428-38 |
| Rosenblum Lichtenstein, Jamie H; Molina, Ramon M; Donaghey, Thomas C et al. (2016) Repeated Mouse Lung Exposures to Stachybotrys chartarum Shift Immune Response from Type 1 to Type 2. Am J Respir Cell Mol Biol 55:521-531 |
| Shore, Stephanie A; Cho, Youngji (2016) Obesity and Asthma: Microbiome-Metabolome Interactions. Am J Respir Cell Mol Biol 54:609-17 |
| Cho, Youngji; Shore, Stephanie A (2016) Obesity, Asthma, and the Microbiome. Physiology (Bethesda) 31:108-16 |
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