- 作者: Hao-Cheng Chen; Horng-Chyuan Lin; Chien-Ying Liu; Chun-Hua Wang; Tritium Hwang; Tzu-Ting Huang; Chien-Huang Lin; Han-Pin Kuo
- 作者服務機構: Department of Thoracic Medicine II, Chang Gung Memorial Hospital Taipei, and Medical Technology, School of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
- 中文摘要: --
- 英文摘要: The sequestration of neutrophils in the lung and therelease of proinflammatory mediators, including neutro-phil elastase, are responsible for sepsis-induced micro-vascular permeability and alveolar epithelial cell dam-age. To assess the underlying mechanism, human neu-trophil elastase《0.01-0.5 ug/ml)was added to culturedA549 epithelial cells in the presence or absence of inhibi-tors. IL-8 was analyzed by ELISA or by RT-PCR to mea-sure the IL-8 synthesis capacity. Mitogen-activated pro-tein kinase(MAPK) activity was detected by Western blotanalysis. Neutrophil elastase dose-dependently in-creased IL-8 release from cultured A549 epithelial cells.Pretreatment with a specific elastase inhibitor, elastaseinhibitor II(at 0.5, 5, and 50 ug/ml),dose-dependentlyinhibited neutrophil elastase-induced IL-8 release. Theactivities of MAPK, p38, and extracellular signal-regu-lated kinase(ERK) were upregulated by neutrophil elas-tase. Nuclear transcriptional factor-kappa B(NF-KB)andactivator protein 1 (AP-1)were also activated.Theseresponses were significantly inhibited by elastase inhibi-for II.A specific inhibitor of p38 MAPK(SB203580)and anNF-KB inhibitor(pyrrolidine dithiocarbamate),but not anERK inhibitor(PD 98059), significantly inhibited neutro-phil elastase-induced IL-8 release and mRNA expression.The specific tyrosine kinase inhibitor, genistein, and theprotein kinase C(PKC) inhibitor, Ro 31-8220, also inhibit-ed IL-8 release and mRNA expression as well as p38 andNF-KB activation. There was no significant effect by theprotein kinase A inhibitor, H-89, on neutrophil elastase-induced IL-8 synthesis or p38 MAPK activation.Ourresults indicate that neutrophil elastase activates p38MAPK which upregulates NF-KB and AP-1 activities, thusinducing IL-8 mRNA expression and protein synthesis.Tyrosine kinase and PKC are implicated in neutrophilelastase activation of the MAPK pathway.
- 中文關鍵字: --
- 英文關鍵字: --