Asthma associated morbidity, disability effects 54 out of every 1000 Americans. This chronic recurrent disease is known to be directly associated with inflammation of the airways. Asthmatic airways are infiltrated with inflammatory cells including eosinophils which are present even in asymptomatic asthmatics with normal lung function. Eosinophils in asthmatic airways are activated and release preformed toxic granular proteins; they contain peroxidases which generate toxic oxygen metabolites, they generate lipid mediators and proinflammatory cytokines which can produce airway hyperresponsiveness-the cardinal physiological feature of asthma. The importance of eosinophils to asthma is suggested by studies that correlate the resolution of asthma symptoms with the resolution of airway eosinophilia. Defining the mechanisms that selectively recruit eosinophils to the airways has the potential to identify novel therapeutic targets relevant to eosinophil mediated diseases including asthma. While many substances are chemotactic for eosinophils far fewer have chemotactic effects that are selective for cell types assoicated with asthma. Eotaxin is one substance that selectively activates these cell types. The discovery of eotaxin in an animal model of asthma has led to investigations of its associations with human disease. Indeed we have recently found that eotaxin is mobilized in asthmatic lungs after segmental allergen challenge and airway levels correlate with the numbers of eosinophils recruited into the lungs. Eotaxin is detectable in human plasma and is directly and independently associated with asthma diagnosis, and inversely related to baseline lung function. Eotaxin levels are increased in asthma exacerbations and elevated levels are associated with worse outcomes from acute asthma care. Our long term goal is to understand the mechanisms that mobilize eotaxin and related chemokines that recruit eosinophils to the airways. We propose to study the mechanisms that are responsible for eotaxin mobilization by studying its mobilization in in vitro systems, and in cells from subjects with common eotaxin polymorphisms that impair eotaxin expression. Specifically we propose: (1) To determine the mechanism(s) by which a coding region polymorphism of the eotaxin gene reduces eotaxin expression. (2) To define the mechanisms that alter eotaxin mRNA expression. (3) To explore mechanisms common to eotaxin and MCP-4 mobilization and define regulatory elements critical for the coordinated expression of these chemokines. This work will lead to a better understanding of the mechanisms by which eotaxin and the CCR3 receptor contribute to the asthamtic diathesis.
| Sonna, Larry A; Kuhlmeier, Matthew M; Khatri, Purvesh et al. (2010) A microarray analysis of the effects of moderate hypothermia and rewarming on gene expression by human hepatocytes (HepG2). Cell Stress Chaperones 15:687-702 |
| Kalayci, Omer; Sonna, Larry A; Woodruff, Prescott G et al. (2004) Monocyte chemotactic protein-4 (MCP-4; CCL-13): a biomarker of asthma. J Asthma 41:27-33 |
| Sonna, Larry A; Wenger, C Bruce; Flinn, Scott et al. (2004) Exertional heat injury and gene expression changes: a DNA microarray analysis study. J Appl Physiol 96:1943-53 |
| Kalayci, Omer; Birben, Esra; Tinari, Nicola et al. (2004) Role of 90K protein in asthma and TH2-type cytokine expression. Ann Allergy Asthma Immunol 93:485-92 |
| Kalayci, Omer; Birben, Esra; Wu, Liqing et al. (2003) Monocyte chemoattractant protein-4 core promoter genetic variants: influence on YY-1 affinity and plasma levels. Am J Respir Cell Mol Biol 29:750-6 |
| Sonna, Larry A; Cullivan, Michael L; Sheldon, Holly K et al. (2003) Effect of hypoxia on gene expression by human hepatocytes (HepG2). Physiol Genomics 12:195-207 |
| Sonna, Larry A; Gaffin, Stephen L; Pratt, Richard E et al. (2002) Effect of acute heat shock on gene expression by human peripheral blood mononuclear cells. J Appl Physiol 92:2208-20 |
| Morse, Brian; Sypek, Joseph P; Donaldson, Debra D et al. (2002) Effects of IL-13 on airway responses in the guinea pig. Am J Physiol Lung Cell Mol Physiol 282:L44-9 |
| Sonna, L A; Sharp, M A; Knapik, J J et al. (2001) Angiotensin-converting enzyme genotype and physical performance during US Army basic training. J Appl Physiol 91:1355-63 |
| Nakamura, H; Luster, A D; Tateno, H et al. (2001) IL-4 differentially regulates eotaxin and MCP-4 in lung epithelium and circulating mononuclear cells. Am J Physiol Lung Cell Mol Physiol 281:L1288-302 |
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