5-Lipoxygenase Products in Asthmatic Immune Response

描述(由申请人提供)：哮喘患者呼吸道的过度炎症和重塑可能是由于支气管上皮对吸入环境的成分敏感而引起的异常损伤和修复反应的结果。在这个环境-基因界面上，通过复杂的细胞因子/趋化因子/生长因子/二十烷类化合物相互作用，上皮细胞和底层间充质细胞被激活，以驱动病理重塑和平滑肌增殖。我们已经在哮喘小鼠模型中证明了半胱氨酰白三烯(CysLT)1受体阻断可以抑制气道重塑过程，包括气道粘液腺和平滑肌细胞增殖、胶原沉积和肺纤维化，以及TH2细胞因子的释放，尽管在确定胞液磷脂酶A2(CPLA2)和分泌型PLA2(SPLA2)S在释放花生四烯酸(AA)中的作用方面取得了相当大的进展，最近发现了几种新的哺乳动物PLA2，评价了特异性PLA2在过敏性气道炎症、重塑和AHR中的作用。这项研究的具体目的如下： 具体目的1.确定sPLA2与cPLA2在慢性哮喘小鼠模型呼吸道炎症和气道高反应性(AHR)调节中的作用。我们将研究sPLA2和cPLA2在哮喘小鼠气道重塑模型中的表达情况，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。 具体目的2.确定选择性阻断哮喘小鼠模型中的CysLT1受体或PLA2是否能逆转已建立的过敏原诱导的呼吸道重塑和纤维化。我们将确定下游(CysLT1受体拮抗剂)与上游(sPLA2或cPLA2抑制)阻断CysLT途径在逆转小鼠哮喘模型已建立的气道重塑方面的相对有效性，并与皮质类固醇治疗进行比较。具体目的3.确定CysLT1受体和PLA2阻断对小鼠气道重塑和纤维化模型中促纤维化基因表达的影响。将进行功能基因组学研究，以确定CysLTs介导变应原诱导的气道重塑的分子机制，重点是炎症反应和转化生长因子(TGF)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.