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变应性气道炎症中发挥重要作用。最近有报道称，除支气管收缩或血管通透性外，这些介质广泛参与哮喘气道的病理改变。由于已知LTC4参与气道重塑，并参与PGD2对Th2型炎症的强化，这两种介质在哮喘发病机制中的新作用已受到关注。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，我们制作了LTC4合酶转基因小鼠。我们澄清了以下几点。LTC4通过活化的T细胞增强Th2细胞因子的产生。IL-13上调半胱氨酸白三烯1受体使人肺成纤维细胞对白三烯C4产生反应并产生eotaxin 2。前列腺素D2通过支气管巨噬细胞来源趋化因子的表达增强气道对低剂量抗原的Th2型炎症反应。BCL6是一种转录抑制因子，调节IL-5基因和LTC4合成酶基因的表达。LTC4和PGD2是Th2型炎症的加重因子。BCL6通过调节IL-5和LTC4合成酶等基因水平抑制哮喘炎症。这些实验结果不仅有望引领支气管哮喘治疗的发展，而且有望进一步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.