Exaggerated inflammation and remodeling in the airways of patients with asthma may be a consequence of abnormal injury and repair responses arising from the bronchial epithelium's susceptibility to components of the inhaled environment. At this environment-gene interface, the epithelium and underlying mesenchymal cells are activated to drive pathologic remodeling and smooth muscle proliferation through complex cytokine/chemokine/ growth factor/eicosanoid interactions. We have demonstrated in a mouse model of asthma that cysteinyl leukotriene (CysLT)1 receptor blockade inhibits the airway remodeling processes, including airway mucus gland and smooth muscle cell hyperplasia, collagen deposition, and lung fibrosis, as well as TH2 cytokine release, although considerable progress has been made in determining the role played by cytosolic phospholipase A2 (cPLA2) and secretory PLA2 (sPLA2)s in release of arachidonic acid (AA) for eicosanoid synthesis, with the recent identification of several new mammalians PLA2s, evaluation of the role of specific PLA2s in the mediation of allergic airway inflammation, remodeling, and AHR is indicated.
The specific aims of this study are as follows:
Specific Aim 1. Determine the Role of sPLA2s vs. cPLA2 in the Mediation of Airway Inflammation and Airway Hyperreactivity (AHR) in a Chronic Mouse Model of Asthma. We will study the profile of sPLA2 and cPLA2 expression in airway cells in a mouse asthma model with airway remodeling and determine the role of these enzymes in AA release and metabolism that leads to development of airway inflammation and AHR.
Specific Aim 2. To Determine Whether Selective CysLT1 Receptor or PLA2 Blockade in a Murine Model of Asthma Reverses Established Allergen-induced Airway Remodeling and Fibrosis. We will determine the relative efficacy of downstream (CysLT1 receptor antagonism) vs. upstream (sPLA2 or cPLA2 inhibition) blockade of the CysLT pathway on reversal of established airway remodeling in the mouse asthma model with comparison also to corticosteroid treatment.
Specific Aim 3. Determine the Effect of CysLT1 Receptor and PLA2 Blockade on Pro-Fibrotic Gene Expression in a Mouse Model of Airway Remodeling and Fibrosis. Functional genomic studies will be performed to determine the molecular mechanisms by which CysLTs mediate allergen-induced airway remodeling focusing on inflammatory response and TGF-(-inducible pro-fibrotic gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042989-09
Application #
7217301
Study Section
Special Emphasis Panel (ZRG1-LBPA (02))
Program Officer
Dong, Gang
Project Start
1998-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
9
Fiscal Year
2007
Total Cost
$331,208
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Henderson Jr, William R; Ye, Xin; Lai, Ying et al. (2013) Key role of group v secreted phospholipase A2 in Th2 cytokine and dendritic cell-driven airway hyperresponsiveness and remodeling. PLoS One 8:e56172
Henderson Jr, William R; Oslund, Rob C; Bollinger, James G et al. (2011) Blockade of human group X secreted phospholipase A2 (GX-sPLA2)-induced airway inflammation and hyperresponsiveness in a mouse asthma model by a selective GX-sPLA2 inhibitor. J Biol Chem 286:28049-55
Hallstrand, Teal S; Henderson Jr, William R (2010) An update on the role of leukotrienes in asthma. Curr Opin Allergy Clin Immunol 10:60-6
Henderson Jr, William R; Chi, Emil Y; Ye, Xin et al. (2010) Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc Natl Acad Sci U S A 107:14309-14
Hallstrand, Teal S; Henderson Jr, William R (2009) Role of leukotrienes in exercise-induced bronchoconstriction. Curr Allergy Asthma Rep 9:18-25
Mehrotra, Anjuli K; Henderson Jr, William R (2009) The role of leukotrienes in airway remodeling. Curr Mol Med 9:383-91
Hallstrand, Teal S; Chi, Emil Y; Singer, Alan G et al. (2007) Secreted phospholipase A2 group X overexpression in asthma and bronchial hyperresponsiveness. Am J Respir Crit Care Med 176:1072-8
Henderson Jr, William R; Chiang, Gertrude K S; Tien, Ying-Tzang et al. (2006) Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. Am J Respir Crit Care Med 173:718-28
Christie, P E; Jonas, M; Tsai, C H et al. (2004) Increase in laminin expression in allergic airway remodelling and decrease by dexamethasone. Eur Respir J 24:107-15
Iwata, Akiko; Nishio, Kazumi; Winn, Robert K et al. (2003) A broad-spectrum caspase inhibitor attenuates allergic airway inflammation in murine asthma model. J Immunol 170:3386-91

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