? In the Severe Asthma Research Program (SARP I), we identified novel reducing-oxidizing (redox) biochemical disorders that characterize severe asthma and defined severe asthma subpopulations based on these abnormalities. There were three major categories of redox abnormalities: (1) impaired regulation of airway acidity, (2) increased oxidation and loss of antioxidant superoxide dismutase (SOD) activity, and (3) alterations of nitric oxide (NO) metabolism with loss of beneficial S-nitrosothiols and formation of cytotoxic reactive nitrogen species. Here, we hypothesize that the pathophysiology of severe asthma is related to abnormalities of enzymes regulating airway redox biochemistry, including CuZnSOD, and two enzymes recently identified to play a role in asthma pathophysiology, arginase and S-nitrosoglutathione reductase (GSNOR). We propose to define how redox abnormalities are interacting determinants of asthma severity and serve as biomarkers for prognosis and evaluation of adequacy of therapy. We will test our hypotheses through three site-specific aims which use the SARP collaborative network and Systemic Triamcinolone in Asthma Characterization (STAC) protocol.
In aim 1, we will 1) validate exhaled breath condensate as a tool for measuring airway inflammation-associated acidification; 2) investigate mechanisms of airway pH dysregulation; and 3) study the relevance of neutralizing airway pH for treatment and prevention of redox-related damage in severe asthma.
In aim 2, we will determine whether or not loss of SOD activity and formation of reactive oxygen species are biomarkers for, and/or determinants of, severe asthma. Mechanisms for loss of activity will be investigated through study of CuZnSOD modifications.
In aim 3, we investigate formation of cytotoxic nitrogen oxides and loss of beneficial nitrogen oxides. As the majority of adult severe asthmatics in SARP I were women, we also investigate gender/estrogen effects on severe asthma and NO. Our preliminary data suggest that NO metabolism, particularly GSNOR expression, is influenced by estrogen. The overarching goals of our studies are 1) development of improved asthma monitoring; and 2) design of innovative therapies tailored to specific biochemical abnormalities in severe asthma patients for whom therapeutic options are limited. At the conclusion of this project, we anticipate that we will be able to identify severe asthma redox phenotypes and to begin to develop therapies specific to individual biochemical disturbances. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069170-08
Application #
7446676
Study Section
Special Emphasis Panel (ZHL1-CSR-L (M1))
Program Officer
Noel, Patricia
Project Start
2001-09-20
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
8
Fiscal Year
2008
Total Cost
$613,561
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Zein, Joe G; Love, Thomas E; Erzurum, Serpil C (2017) Asthma Is Associated with a Lower Risk of Sepsis and Sepsis-related Mortality. Am J Respir Crit Care Med 196:787-790
Fitzpatrick, Anne M (2016) Severe Asthma in Children: Lessons Learned and Future Directions. J Allergy Clin Immunol Pract 4:11-9; quiz 20-1
Teodorescu, Mihaela; Broytman, Oleg; Curran-Everett, Douglas et al. (2015) Obstructive Sleep Apnea Risk, Asthma Burden, and Lower Airway Inflammation in Adults in the Severe Asthma Research Program (SARP) II. J Allergy Clin Immunol Pract 3:566-75.e1
Zein, Joe G; Dweik, Raed A; Comhair, Suzy A et al. (2015) Asthma Is More Severe in Older Adults. PLoS One 10:e0133490
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
Voraphani, N; Gladwin, M T; Contreras, A U et al. (2014) An airway epithelial iNOS-DUOX2-thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma. Mucosal Immunol 7:1175-85
Wysocki, Kenneth; Park, Seo Young; Bleecker, Eugene et al. (2014) Characterization of factors associated with systemic corticosteroid use in severe asthma: data from the Severe Asthma Research Program. J Allergy Clin Immunol 133:915-8
Witt, Chad A; Sheshadri, Ajay; Carlstrom, Luke et al. (2014) Longitudinal changes in airway remodeling and air trapping in severe asthma. Acad Radiol 21:986-93
Wu, Wei; Bleecker, Eugene; Moore, Wendy et al. (2014) Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J Allergy Clin Immunol 133:1280-8
Holguin, Fernando; Comhair, Suzy A A; Hazen, Stanley L et al. (2013) An association between L-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype. Am J Respir Crit Care Med 187:153-9

Showing the most recent 10 out of 75 publications