Roles of leukotrienes in the development of wheeze in infants

本研究的目的是(1)阐明环境因素如何参与病毒诱导的婴儿喘息的发生，以及(2)阐明这些因素如何影响这些受试者的花生四烯酸代谢和这些代谢物的受体。我们还研究了早期使用某些抗炎药物，如吸入类固醇和白三烯受体拮抗剂是否可以抑制哮喘的发展。我们建立了包括正常细胞在内的人气管支气管细胞培养细胞系。我们发现这些气管支气管细胞表达半胱氨酰白三烯受体(cysLTR1和cysLTR2)和白三烯B4(BLT)受体。通过使用这些细胞系，我们进行了以下实验：首次将人工合成的聚肌胞苷酸：Poly IC(DsRNA)作为病毒感染的模型导入这些细胞中。Poly IC可显著诱导RANTES、IL-8和eoaxin-3的表达和蛋白合成。我们还发现，加入IL-4和IL-13、Th2细胞因子后，嗜酸性粒细胞趋化因子3mRNA和蛋白质合成的表达呈剂量和时间依赖性增加。当dsRNA孵育24小时后用IL-4刺激细胞时，嗜酸性粒细胞趋化因子3的诱导量增加。这种增强的机制是dsRNA对IL+C257-4受体(IL-4Ra和IL-2RR)分子的新诱导。我们发现在半胱氨基白三烯的存在下，嗜酸性粒细胞趋化因子3的产生进一步增加，并被白三烯受体拮抗剂抑制，这表明呼吸道和半胱氨基白三烯的病毒感染与婴儿喘息的发生有关。

The aims of this study are (1) to clarify how environmental factors are involved in the development of virus-induced wheezing in infants, and(2) to elucidate how these factors influence arachidonic acid-metabolism and receptors of these metabolites in these subjects. We also investigate whether asthma development can be inhibited by early use of certain anti-inflammatory drugs such as inhaled steroids and leukotoriene receptor antagonists.We have established the cultured cell lines of human tracheobronchial cells including normal cells. We found that these tracheobronchial cells express receptors of cysteinyl leukotrienes (cysLTR1 and cysLTR2) and leukotrieneB4 (BLT). By using these cell lines, we have conducted the following experiments.We firstly transfected artificially synthesized poly inosinic-cytidyric acid: poly IC (dsRNA) into these cells as a model of virus infection. Transfection of poly IC strongly induced the expression of mRNA and protein synthesis of RANTES, IL-8 and eotaxin-3. We also found that the expression of mRNA and protein synthesis of eotaxin 3 is dose- and time-dependently increased by addition of IL-4 and IL-13, Th2 cytokines. When cells are stimulated with IL-4 after 24 hour-incubation of dsRNA, the induction of eotaxin 3 was additively increased. The mechanism of this enhancement is a new induction of the molecules of IL+C257-4 receptors (IL-4Ra and IL-2Rr) by dsRNA. We found that the production of eotaxin 3 is further increased in the presence of cysteinyl leukotrien and inhibited by leukotriene receptor antagonist, indicating that viral infection of respiratory tract and cysteinyl leukotrienes is associated with the development of wheezing in infants.