Asthma is a highly prevalent airway disease that is a major public health problem for which available treatment options are inadequate. Endogenous nitrated fatty acids (NFAs), thought to be produced from NO, have recently been identified as important bioactive compounds present in human plasma. Although investigation of their biological activities is at an early stage, evidence is accumulating that they are potent anti-inflammatory molecules. Our preliminary data show that administration of exogenous NFAs can significantly attenuate pathophysiologic manifestations in a murine model of allergic airway disease, whereas inhibiting endogenous NFA synthesis exacerbates allergic responses. NFAs activate the nuclear transcription factor peroxisome proliferator-activated receptor-? (PPAR-?) in some cell types, and we have found that allergic responses are exacerbated when PPAR-? is genetically eliminated but are attenuated by overexpression of PPAR-? in airway epithelial cells in vivo. Accordingly, we propose to test the hypothesis that activation of airway epithelial cell PPAR-? by nitrated fatty acids significantly suppresses the effects of allergic airway disease, including inflammation and mucus production.
Our Specific Aims are: 1) to determine the extent to which NFAs modulate PPAR-? activity in the lung and the severity of murine allergic airway disease, for which we will use mice constitutively lacking all three isoforms of nitric oxide synthase (triple NOS knockout) and therefore expected to lack NFAs;2) to determine whether PPAR-? activation in airway epithelial cells mediates NFAs'ability to inhibit effects of allergen challenge in murine allergic airway disease, for which we will utilize mice with PPAR-? either knocked out or overexpressed selectively in airway epithelial cells;and 3) to determine whether NFAs inhibit chemokine and mucus production in cultured human airway epithelial cells and the extent to which these effects are mediated through PPAR-?-dependent and/or PPAR-?-independent mechanisms, for which we will use gene silencing and chemical inhibition to suppress PPAR-? while testing for activation of other signaling pathways.
For Aims 1 and 2 we will utilize an established murine model of allergic airway disease induced by cockroach allergen, while Aim 3 will be carried out in vitro using well differentiated primary human bronchial epithelial cells grown at an air-liquid interface. Validation of our hypothesis will identify and elucidate the mechanisms through which a novel endogenous substance modulates the severity of allergic airway disease and may lead to new therapeutic avenues and treatments for asthma.

Public Health Relevance

Asthma is a serious, highly-prevalent lung disease. Our research will determine whether substances recently identified within our bodies reduce allergic airway responses. We will determine the mechanisms by which these substances act, leading to a better understanding of the processes underlying asthma and possibly to development of new approaches and agents for asthma therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093196-05
Application #
8243538
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2009-04-01
Project End
2012-10-06
Budget Start
2012-04-01
Budget End
2012-10-06
Support Year
5
Fiscal Year
2012
Total Cost
$319,523
Indirect Cost
$72,023
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lakshmi, Sowmya P; Reddy, Aravind T; Zhang, Yingze et al. (2014) Down-regulated peroxisome proliferator-activated receptor ? (PPAR?) in lung epithelial cells promotes a PPAR? agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD). J Biol Chem 289:6383-93
Reddy, Aravind T; Lakshmi, Sowmya P; Dornadula, Sireesh et al. (2013) The nitrated fatty acid 10-nitro-oleate attenuates allergic airway disease. J Immunol 191:2053-63
Narala, Venkata R; Adapala, Ravi K; Suresh, Madathilparambil V et al. (2010) Leukotriene B4 is a physiologically relevant endogenous peroxisome proliferator-activated receptor-alpha agonist. J Biol Chem 285:22067-74
Reddy, Raju C; Standiford, Theodore J (2010) Effects of sepsis on neutrophil chemotaxis. Curr Opin Hematol 17:18-24