This is a three-university consortium lead by Serpil Eruzrum, MD, Cleveland Clinic, which includes Anne Fitzpatrick, PhD, Emory University, and Benjamin Gaston, MD and W. Gerald Teague, MD at The University of Virginia. The focus of this aligned effort is to understand the role of airway redox epithelial determinants of severe asthma in both adults and children. Ongoing studies involve detailed characterization procedures which are common to all SARP sites, with added emphasis on the airway redox pathways. At Cleveland Clinic the primary focus is on nitric oxide (NO), its synthesis and metabolism, with a detailed analysis of both systemic and airway arginase activities, and oxidative modification of factors which determine NO synthesis. At Emory University the main focus has been on assembling a large cohort of children with severe asthma, with extensive characterization procedures in an attempt to understand specific phenotypes which define severe asthma in childhood.  Related studies at Emory have evaluated innate immunity in severe asthma of childhood, with particular emphasis on the role of the alveolar macrophage. At The University of Virginia the focus has been on the fundamental airway protective compound S-nitrosoglutathione and specific mechanisms which result in its depletion.  A common interest of this group of investigators is to develop novel therapies for severe asthma based on restoration of a normal airway redox environment.


Cleveland Clinic Information for Medical and Academic Professionals

The University of Virginia site is under the leadership of Benjamin W. Gaston, MD, and W. Gerald Teague, MD, SARP co-investigators, and is aligned with The Cleveland Clinic and Emory University sites in a joint effort that focuses on the airway epithelial and systemic redox determinants of severe asthma. A second aim at UVa is to improve the understanding of severe asthma in childhood through detailed phenotypic characterization of children with poorly controlled asthma. Specific studies include clinical and bench laboratory work to understand the role of GSNO catabolism in the airway, an important endogenous s-nitrosothiol that is highly protective and involved with the regulation of airway muscle tone.

SARP Co-investigator

 

Benjamin W. Gaston MD

Professor of Pediatrics

Pediatric Respiratory Medicine

PO Box 800386

University of Virginia School of Medicine

Charlottesville, VA 22901

bm3g@virginia.edu

 

Dr. Gaston has been involved in nitric oxide research for many years, particularly the role of NO signaling in airway, vascular, and CNS biology. With regards to human asthma, Dr. Gaston along with Dr. John Hunt at UVa discovered that acute exacerbations are associated with a decrease in airway pH. This finding is important in that low pH supports the formation of toxic oxidation products of NO in the airways and likewise affects the redox status of endogenous thiols. Within the SARP program Dr. Gaston has shown that inhalation of airway buffer (hence restoration of pH) acutely decreases the magnitude of exhaled nitric oxide by favoring the formation of nitrites at higher pH. This effect is enhanced in individuals with asthma versus healthy controls. Dr. Gaston has gone on in preliminary studies based on the adult and pediatric SARP population to find that low pH is associated with high BMI, BAL fluid neutrophilia, low expired NO, and GERD. Current studies underway are focusing on NO signaling pathways in persistent asthma, particularly the status of endogenous GSNO in the airways and its catabolism.

SARP Co-investigator

 

W. Gerald Teague MD

Professor of Pediatrics

PO Box 800386

Pediatric Respiratory Medicine

University of Virginia School of Medicine

Charlottesville, VA 22901

wgt2p@virginia.edu

 

Dr. Teague has also been a co-investigator within SARP from its inception, and has primarily been involved in clinical characterization studies to understand the features of severe versus mild to moderate asthma in children. This work started at Emory University which was the lead site within the SARP for recruitment of pediatric-age subjects. He has reported along with Anne Fitzpatrick, PhD that severe asthma can be recognized early in childhood, and is differentiated by ongoing symptoms despite treatment with high-dose corticosteroids, mild airflow obstruction with air trapping, yet near complete reversibility of lung function to the normal range with high dose bronchodilators.  Furthermore children with severe asthma have a more homogeneous phenotype compared to adults, and have a higher prevalence of atopy and higher expired NO. Current studies are ongoing in collaboration with Wake Forest University to better understand the classification of different phenotypes in children with severe asthma, and to identify noninvasive biomarkers within the NO pathways which predict severe asthma. In this way the SARP team at UVa plans to explore novel therapies for adults and children with severe asthma to restore the protective effect of endogenous s-nitrosothiols.