The Metabolic Syndrome (MS) is an independent risk factor for inflammatory diseases of the lung, and improved understanding of the mechanism by which MS contributes to lung inflammation offers hope for the development of new treatment strategies. Chronic, low grade systemic inflammation is a component of MS that may promote lung inflammation in part through the proinflammatory properties of uric acid (UA), which is increased in MS patients. Presently, the role of UA in ALI/ARDS is poorly understood and is confounded by comorbidity factors commonly associated with MS such as hyperglycemia or insulin resistance that may also affect lung inflammation. We recently developed a conditional knockout of XOR in mice that enables us to investigate the specific role of serum UA in mouse models of ALI/ARDS. This grant will advance our knowledge of MS mediated inflammatory lung disease by characterizing the role of XOR and UA in novel robust mouse models of MS that will be validated by prospective analysis of MS associated inflammatory lung disease in humans.
Our aims are (1) To determine whether serum UA contributes to mouse models of ALI/ARDS by knocking out hepatocyte XOR using a newly generated XORfl/fl mouse strain that will be treated with hepatocyte targeted Cre recombinase. These experiments will be contrasted to mice made hyperuricemic by fructose feeding. ALI/ARDS will be induced using Th1 cytokine or LPS insufflation subsequent to XOR ablation. (2) To determine whether serum UA contributes to ALI/ARDS in a genetic model of hyperuricemia we will knockout hepatocyte XOR in Leprdb-lb mice that will be treated with hepatocyte targeted anti-XOR-shRNA prior to cytokine or LPS insufflation. These experiments will be contrasted to Leprdb-lb mice treated with systemic pharmacological inhibitors of XOR prior to LPS or Th1 cytokine insufflation. (3) To determine whether serum UA is predictive of clinical outcome in ALI/ARDS patients presenting with MS we will screen human patient data developed at the University of Colorado Hospital ICU to correlate serum UA with patient outcome for MS patients exhibiting ALI/ARDS. Data produced by this study may recommend UA as an important parameter for measurement in human clinical trials and may indicate its relevance as a therapeutic target in the management of MS associated lung inflammatory disorders.

Public Health Relevance

The Metabolic Syndrome (MS) is an independent risk factor for inflammatory diseases of the lung, and improved understanding of the mechanism by which MS contributes to lung inflammation offers hope for the development of new treatment strategies. Chronic, low grade systemic inflammation is a component of MS that may promote lung inflammation in part through the proinflammatory properties of uric acid (UA), which is increased in MS patients. This grant application will advance our knowledge of MS mediated inflammatory lung disease by characterizing the role of XOR and UA in novel robust mouse models of MS that will be validated by prospective analysis of MS associated inflammatory lung disease in humans. Data produced by this study may recommend UA as an important parameter for measurement in human clinical trials and may indicate its relevance as a therapeutic target in the management of MS associated lung inflammatory disorders

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL113809-01A1
Application #
8444228
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2013-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$231,438
Indirect Cost
$81,438
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Kanbay, Asiye; Inonu, Handan; Solak, Yalcin et al. (2014) Uric acid as a potential mediator of cardiovascular morbidity in obstructive sleep apnea syndrome. Eur J Intern Med 25:471-6
Fini, Mehdi A; Wright, Richard M; Stenmark, Kurt R et al. (2014) Is uric acid an underdiagnosed mediator of adverse outcome in metabolically healthy overweight/obese individuals? Am J Med 127:e21