Abstract
Cysteinyl leukotrienes (cysLTs), arachidonate 5-lipoxygenase products, play significant roles in the pathogenesis of bronchial asthma in children. In these 15 years several lines of evidence have demonstrated that the production of cysLTs is controlled by molecular mechanisms induced by external and internal bioactive substances. A direct evidence is that levels of cysLTs and LTB4 in BALF were markedly increased in asthmatic children with acute exacerbation. Peripheral polymorphonuclear leukocytes obtained from asthmatic children produced higher levels of cysLTs and LTB4 than those from controls, which also supported this hypothesis. The increased production of cysLTs and LTB4 is attributable to transcriptional and/or post-transcriptional up-regulation of LT-synthetic enzymes, 5-lipoxygenase, LTA4 hydrolase and LTC4 synthase. Activity of cysLT-catabolic enzymes in vivo is also determined by degradation of cysLTs. LTC4 is metabolized to less bioactive LTE4 via LTD4 by two consecutive catabolic enzymes, gamma-glutamyl leukotrienase (gamma-glutamyl transpeptidase related enzyme; GTPRE) and dipeptidase. GTPRE was found to be transcriptionally up-regulated by glucocorticosteroid (GCS) in transformed human bronchial epithelial cells. Accelerated conversion of LTC4 to LTE4 by GCS-induced GTPRE explains, in part, the efficacy of GCS in the treatment of bronchial asthma. Thus, leukotriene metabolism is controlled by transcriptional and/or post-transcriptional regulatory mechanisms at various steps of synthetic and catabolic enzymes, which contributes to pathophysiology of childhood asthma.
