5-Lipoxygenase Products in Asthmatic Immune Response

描述（由申请方提供）：哮喘患者气道的炎症和重塑加重可能是支气管上皮对吸入环境组分的易感性引起的异常损伤和修复反应的结果。 在这种环境-基因界面，上皮和下层间充质细胞被激活，通过复杂的细胞因子/趋化因子/生长因子/类花生酸相互作用驱动病理性重塑和平滑肌增殖。 我们已经在哮喘小鼠模型中证明，半胱氨酰白三烯（CysLT）1受体阻断剂抑制气道重塑过程，包括气道粘液腺和平滑肌细胞增生、胶原沉积和肺纤维化，以及TH 2细胞因子释放，尽管在确定胞浆磷脂酶A2（cPLA 2）和分泌型PLA 2（sPLA 2）所起的作用方面已经取得了相当大的进展，近年来，随着近年来对几种新的类花生酸PLA 2的鉴定，特别是对PLA 2在过敏性气道炎症、气道重塑和AHR中的作用进行了研究。这项研究的具体目标如下： 具体目标1。 确定sPLA 2与cPLA 2在慢性哮喘小鼠模型中气道炎症和气道高反应性（AHR）介导中的作用。 我们将研究sPLA 2和cPLA 2在小鼠哮喘模型气道重塑气道细胞中的表达谱，并确定这些酶在AA释放和代谢中的作用，从而导致气道炎症和AHR的发展。 具体目标2。确定在哮喘小鼠模型中选择性CysLT 1受体或PLA 2阻断是否逆转过敏原诱导的气道重塑和纤维化。 我们将确定CysLT通路的下游（CysLT 1受体拮抗）与上游（sPLA 2或cPLA 2抑制）阻断对逆转小鼠哮喘模型中已建立的气道重塑的相对疗效，并与皮质类固醇治疗进行比较。 具体目标3。确定CysLT 1受体和PLA 2阻断对气道重塑和纤维化小鼠模型中促纤维化基因表达的影响。将进行功能基因组研究以确定CysLT介导变应原诱导的气道重塑的分子机制，重点是炎症反应和TGF-β诱导的促纤维化基因表达。

DESCRIPTION (provided by applicant): 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.