Abstract:
BACKGROUND:Elastase released from activated neutrophils is an important mediator of inflammatory tissue damage. We investigated the effect of human neutrophil elastase (NE) inhibitor (ONO-5046) on reperfusion injury after pancreaticoduodenal transplantation in rats by measuring the expression of intercellular adhesion molecule-1 (ICAM-1). Additional in vitro experiments were conducted to investigate the effect of NE on ICAM-1 mRNA transcription in a rat endothelial cell line (WK-5) and human umbilical vein endothelial cells (HUVEC). METHODS:In an in vivo experiment, male Wistar rats were transplanted with syngeneic pancreaticoduodenal grafts. An NE inhibitor, ONO-5046, was injected intravenously 5 min before vascular clamping and immediately after reperfusion at a dose of 10 mg/kg. ICAM-1 expression was determined by immunostaining and Northern analysis. In in vitro experiments, the effects of NE and chemical agents on ICAM-1 mRNA transcripts were determined in WK-5 cells and HUVEC. RESULTS:Pretreatment with ONO-5046 decreased ICAM-1 immunostaining in the pancreatic graft and inhibited the increase in ICAM-1 mRNA levels in grafts after reperfusion. ICAM-1 mRNA levels in WK-5 cells and HUVEC showed stimulation by NE, while ONO-5046 inhibited this increase. Calcium ionophore (A23187) augmented NE stimulation of ICAM-1 mRNA levels in these cells. In contrast, a phospholipase C inhibitor (U73122) blunted NE induction of ICAM-1 mRNA, and either calcium chelator (TMB-8) or a nuclear factor-kappa B inhibitor (pyrrolidine dithiocarbamate) completely inhibited induction. CONCLUSION:These results indicate that NE stimulates ICAM-1 expression in pancreatic grafts via intracellular Ca2+ influx and a phospholipase C signal transduction.
journal_name
Transplantationjournal_title
Transplantationauthors
Yamaguchi Y,Matsumura F,Wang FS,Akizuki E,Liang J,Matsuda T,Okabe K,Ohshiro H,Horiuchi T,Yamada S,Mori K,Ogawa Mdoi
10.1097/00007890-199806270-00014subject
Has Abstractpub_date
1998-06-27 00:00:00pages
1622-8issue
12eissn
0041-1337issn
1534-6080journal_volume
65pub_type
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