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Functinal analysis of leukotrine C4 synthase gene in the pathogenesis of asthma

白三碱C4合酶基因在哮喘发病机制中的功能分析

基本信息

批准号：
12470137
负责人：
FUKUDA Takeshi
金额：
$ 9.15万
依托单位：
Dokkyo University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Mast cells play important roles in allergic airway inflammation by releasing several type cytokines and chemical mediators. Recently it has been reported that these mediators participate broadly in the pathological changes of asthmatuc airways, in addition to bronchial contraction or a blood vessel permeability. Because LTC4 is known to be involved in airway remodeling, and in reinforcement of Th2 type inflammation with PGD2, novel actions of these two mediators have been paid attentions for the pathogenesis of asthma. In this research, we analyzed the roles of LTC4 and PGD2 on asthmatic airway inflammation. For this purpose we made a LTC4 synthase transgenic mice. We have clarified about the following points.1.LTC4 erinforced production of Th2 cytokine by activated T cells. And up-regulation of cysteinyl leukotriene 1 receptor by IL-13 enables human lung fibroblasts to respond to leukotriene C4 and produce eotaxin.2.Prostaglandin D2 reinforces Th2 type inflammatory responses of airways to low-dose antigen through bronchial expression of macrophage-derived chemokine.3.A transcriptional repressor, BCL6 regulate expression of IL-5 gene and LTC4 synthase gene.It becomes clear that the LTC4 and PGD2 are aggravation factor of Th2 type inflammation. Moreover, BCL6 is adjusted to restrain to asthmatic inflammation on the gene level of which are IL-5 and LTC4 synthase. It is expectable to lead not only development of the treatment for bronchial asthma, but also to elucidate of the pathogenesis of asthma by these experimental results.

肥大细胞通过释放多种细胞因子和化学介质在过敏性气道炎症中发挥重要作用。近年来有研究表明，这些介质除了引起支气管收缩或血管通透性增加外，还广泛参与哮喘气道的病理变化。由于已知LTC 4参与气道重塑，并与PGD 2一起加强Th 2型炎症，因此这两种介质在哮喘发病机制中的新作用受到关注。本研究旨在探讨LTC 4和PGD 2在哮喘气道炎症中的作用。为此，我们制作了LTC 4合酶转基因小鼠。我们阐明了以下几点：1.LTC4增强活化的T细胞产生Th 2细胞因子。IL-13上调半胱氨酰白三烯1受体使人肺成纤维细胞对白三烯C4产生应答并产生嗜酸性粒细胞趋化因子。2.前列腺素D2通过支气管表达巨噬细胞源性趋化因子增强气道对低剂量抗原的Th 2型炎症反应。BCL 6调节IL-5基因和LTC 4合酶基因的表达，提示LTC 4和PGD 2是Th 2型炎症的加重因子。此外，BCL 6在基因水平上通过调节IL-5和LTC 4合酶而抑制哮喘炎症反应。这些实验结果不仅对支气管哮喘治疗的发展，而且对阐明哮喘的发病机制具有重要意义。