Roles of leukotrienes in the development of wheeze in infants

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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.