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, Inflammation and cardiovascular disease risk that involves post-translational modification of proteins via carbamylation, 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 substantially elevated by smoking (>5 fold) and second hand tobacco smoke exposure (>2-fold). Strikingly greater increase In protein carbamylation occurs within asthmatic airways 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 In unpublished studies we show that eosinophil peroxidase, a related member of the heme peroxidase superfamily known to be enriched and active within human asthmatic airways, is much more efficient than MPO at promoting protein carbamylation at normal plasma levels of SCN". EPO-catalyzed protein carbamylation induces multiple asthma-associated phenotypes including induction of airway epithelial cell apoptosis, MUC5AC expression and mucin accumulation. Protein carbamylation 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 airways, plasma and urine of asthmatics and relate this to disease severity and exposure to ETS. Using mouse models of allergen induced 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 airway epithelial cell apoptosis in primary human and mouse cells in vitro and in wild type 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 innovative approaches to Improve asthma care.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-A)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
United States
Zip Code
Navaneethan, Udayakumar; Parsi, Mansour A; Lourdusamy, Vennisvasanth et al. (2015) Volatile organic compounds in bile for early diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis: a pilot study. Gastrointest Endosc 81:943-9.e1
Cowan, Douglas C; Taylor, D Robin; Peterson, Laura E et al. (2015) Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol 135:877-83.e1
Tang, W H Wilson; Wang, Zeneng; Shrestha, Kevin et al. (2015) Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure. J Card Fail 21:91-6
Alkhouri, N; Eng, K; Cikach, F et al. (2015) Breathprints of childhood obesity: changes in volatile organic compounds in obese children compared with lean controls. Pediatr Obes 10:23-9
Lauer, Mark E; Aytekin, Metin; Comhair, Suzy A et al. (2014) Modification of hyaluronan by heavy chains of inter-?-inhibitor in idiopathic pulmonary arterial hypertension. J Biol Chem 289:6791-8
Ratanamaneechat, Suphagaphan; Neumann, Donald R; Difilippo, Frank P et al. (2014) Redox imaging of inflammation in asthma. Am J Respir Crit Care Med 189:743-6
Kennedy, David J; Fan, Yiying; Wu, Yuping et al. (2014) Plasma ceruloplasmin, a regulator of nitric oxide activity, and incident cardiovascular risk in patients with CKD. Clin J Am Soc Nephrol 9:462-7
Tang, W H Wilson; Topol, Eric J; Fan, Yiying et al. (2014) Prognostic value of estimated functional capacity incremental to cardiac biomarkers in stable cardiac patients. J Am Heart Assoc 3:e000960
Navaneethan, Sankar D; Wehbe, Edgard; Heresi, Gustavo A et al. (2014) Presence and outcomes of kidney disease in patients with pulmonary hypertension. Clin J Am Soc Nephrol 9:855-63
Xu, Weiling; Janocha, Allison J; Leahy, Rachel A et al. (2014) A novel method for pulmonary research: assessment of bioenergetic function at the air-liquid interface. Redox Biol 2:513-9

Showing the most recent 10 out of 25 publications