Second hand tobacco smoke exposure is the single largest risk factor for asthma-related morbidity and mortality. Remarkably, the mechanisms contributing to asthma exacerbations and progression of disease following either acute or chronic environmental tobacco smoke exposure (ETS) are not fully understood. We discovered a novel mechanism linking smoking exposure, Inflammafion and cardiovascular disease risk that nvolves post-translafional modificafion of proteins via carbamylafion, a chemical process facilitated by the leukocyte peroxidase myeloperoxidase (MPO) In the presence of thiocyanate (SCN""""""""), an anion normally found in plasma whose levels are substanfially elevated by smoking (>5 fold) and second hand tobacco smoke exposure (>2-fold). Strikingly greater increase In protein carbamylation occurs within asthmatic ainways of humans, and in animal (mouse) models of asthma following allergen challenge. In unpublished studies we show that eosinophil peroxidase, a related member of the heme peroxidase superfamily known to be enriched and active witiiin human asthmatic ainways, is much more efficient than MPO at promoting protein carbamylation at normal plasma levels of SCN"""""""". EPO-catalyzed protein carbamylation induces mulfiple asthma-associated phenotypes including induction of ainway epithelial cell apoptosis, MUC5AC expression and mucin accumulafion. Protein carbamylafion co-localizes with EPO In lung biopsies from asthmatic subjects. Our overall hypothesis is that protein carbamylation Is a fundamental process intrinsic to eosinophilic Inflammatory disorders and serves as a mechanism linking smoking and asthma pathogenesis in humans. To test this, we will examine levels of carbamylated protein in the ainways, plasma and urine of asthmatics and relate this to disease severity and exposure to ETS. Using mouse models of allergeninduced asthma we will determine if EPO is the major heme peroxidase responsible for generating carbamylated protein In the asthmatic lung and examine if ETS alters this. Finally, we will examine if carbamylated protein alone can elicit many of the pathopysiological asthma phenotypes, such as mucus plugging and ainway epithelial cell apoptosis in primary human and mouse cells in vitro and in wildtype and SR-AI KO animals in vivo. The information obtained will be used to define novel targets for treatment of asthma (e.g. SR-AI decoy receptors), and identify molecular (diagnostic) biomarkers for monitoring inflammatory in asthma that may help guide tailored therapeutic regimens. Project 1 works closely with the three other projects and cores towards mechanistic understanding of asthma that Is directed towards design of innovafive approaches to Improve asthma care.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL103453-02
Application #
8379900
Study Section
Special Emphasis Panel (ZHL1-CSR-A)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$466,018
Indirect Cost
$160,115
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Ghosh, Arnab; Stuehr, Dennis J (2017) Regulation of sGC via hsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives. Antioxid Redox Signal 26:182-190
Israel, Laura; Wang, Ying; Bulek, Katarzyna et al. (2017) Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity. Cell 168:789-800.e10
Zepp, Jarod A; Zhao, Junjie; Liu, Caini et al. (2017) IL-17A-Induced PLET1 Expression Contributes to Tissue Repair and Colon Tumorigenesis. J Immunol 199:3849-3857
Modena, Brian D; Bleecker, Eugene R; Busse, William W et al. (2017) Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease. Am J Respir Crit Care Med 195:1449-1463
Chen, Jiwang; Sysol, Justin R; Singla, Sunit et al. (2017) Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension. Circulation 135:1532-1546
Stober, Vandy P; Johnson, Collin G; Majors, Alana et al. (2017) TNF-stimulated gene 6 promotes formation of hyaluronan-inter-?-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness. J Biol Chem 292:20845-20858
Gu, Xiaodong; Huang, Ying; Levison, Bruce S et al. (2016) Identification of Critical Paraoxonase 1 Residues Involved in High Density Lipoprotein Interaction. J Biol Chem 291:1890-904
Martin, Bradley N; Wang, Chenhui; Zhang, Cun-jin et al. (2016) T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis. Nat Immunol 17:583-92
Reeves, Stephen R; Kaber, Gernot; Sheih, Alyssa et al. (2016) Subepithelial Accumulation of Versican in a Cockroach Antigen-Induced Murine Model of Allergic Asthma. J Histochem Cytochem 64:364-80
Cheong, Hoi I; Asosingh, Kewal; Stephens, Olivia R et al. (2016) Hypoxia sensing through ?-adrenergic receptors. JCI Insight 1:e90240

Showing the most recent 10 out of 121 publications