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.
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