Severe asthma affects 5-10% of asthmatics. It is associated with a poor quality of life, high risk for mortality, and accounts for a disproportionate share of the economic cost related to asthma. It is characterized by persistent airway inflammation despite corticosteroid therapy. Further, this inflammatory process is notable for a marked neutrophilia that differs from the eosinophil predominant inflammation characteristic of mild-moderate asthma. Lipoxins and epi-lipoxins are a class of small endogenous molecules that downregulate inflammatory responses including mobilization of neutrophils and eosinophils. They can be produced by cells in the lung and we have shown variability among asthmatics in their ability to synthesize these molecules. In view of the character of airway inflammation in severe asthma, and the known properties of the lipoxins, we hypothesize the following: In patients with mild-moderate asthma, lipoxins and 15-epi-lipoxins function as endogenous counterregulatory signals that dampen airway inflammation. In a subset of patients with severe asthma, defective counterregulatory signaling by this pathway accounts for persistent inflammation. To explore the role of these counter-regulatory molecules in severe asthma, we propose four Specific Aims: 1. Identify and characterize patients with severe asthma and a matched cohort with mild-to-moderate asthma; (2) Characterize LX and 15-epi-LX biosynthesis and receptor expression in severe asthma; (3) Determine if DNA sequence variants in genes of the LX and 15-epi-LX counterregulatory pathways are associated with asthma severity; and (4) Examine the functional significance of polymorphisms in candidate genes associated with asthma severity. We will draw on the complementary expertise of our investigators, who have collaborated on a variety of projects related to asthma, on the established asthma recruitment and phenotyping resources available at this site through the Asthma Clinical Research Network and on the genomic resources available through the Program in Genomic Applications, and the Pharmacogenetics Research Network. Elucidation of the roles played by lipoxins and epi-lipoxins in severe asthma and the genetic basis for differences in this counter-regulatory pathway among individuals would enhance our understanding of the pathogenesis of severe asthma. Such information may ultimately lead to new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL069349-01
Application #
6439227
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Noel, Patricia
Project Start
2001-09-20
Project End
2006-06-30
Budget Start
2001-09-20
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$599,616
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Rao, Chitra K; Moore, Charity G; Bleecker, Eugene et al. (2013) Characteristics of perimenstrual asthma and its relation to asthma severity and control: data from the Severe Asthma Research Program. Chest 143:984-992
Kazani, Shamsah; Planaguma, Anna; Ono, Emiko et al. (2013) Exhaled breath condensate eicosanoid levels associate with asthma and its severity. J Allergy Clin Immunol 132:547-553
Li, Xingnan; Hawkins, Gregory A; Ampleford, Elizabeth J et al. (2013) Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients. J Allergy Clin Immunol 132:313-20.e15
Jarjour, Nizar N; Erzurum, Serpil C; Bleecker, Eugene R et al. (2012) Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Am J Respir Crit Care Med 185:356-62
Li, Xingnan; Ampleford, Elizabeth J; Howard, Timothy D et al. (2012) Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases. J Allergy Clin Immunol 130:861-8.e7
Li, Xingnan; Ampleford, Elizabeth J; Howard, Timothy D et al. (2012) The C11orf30-LRRC32 region is associated with total serum IgE levels in asthmatic patients. J Allergy Clin Immunol 129:575-8, 578.e1-9
Luyster, Faith S; Teodorescu, Mihaela; Bleecker, Eugene et al. (2012) Sleep quality and asthma control and quality of life in non-severe and severe asthma. Sleep Breath 16:1129-37

Showing the most recent 10 out of 30 publications