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

肥大细胞通过释放多种类型的细胞因子和化学介质，在过敏性气道炎症中发挥重要作用。最近有报道称，除了支气管收缩或血管通透性外，这些介质还广泛参与哮喘呼吸道的病理变化。由于LTC4参与了气道重塑和PGD2对Th2型炎症的强化作用，因此这两种介质在哮喘发病机制中的新作用引起了人们的关注。在本研究中，我们分析了LTC4和PGD2在哮喘气道炎症中的作用。为此，我们制备了LTC4合酶转基因小鼠。我们澄清了以下几点：1.LTC4诱导活化的T细胞产生Th2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产生反应，产生嗜酸性粒细胞趋化因子。2.前列腺素D2通过巨噬细胞源性趋化因子的表达，增强低剂量抗原引起的呼吸道Th2型炎症反应。3.转录抑制因子BCL6调节IL-5基因和LTC4合酶基因的表达，LTC4和PGD2是Th2型炎症的加重因子。此外，BCL6还在IL-5和LTC4合成酶的基因水平上被调整为抑制哮喘炎症。这些实验结果不仅有望引导哮喘治疗的发展，而且有望阐明哮喘的发病机制。

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.