Hepatocyte growth factor increases in injured organs and functions as an organotrophic factor in rats with experimental acute pancreatitis.
We previously reported that serum hepatocyte growth factor (HGF) levels are elevated in patients with acute pancreatitis and that pancreatitis-associated ascitic fluid (PAAF) contains cytotoxic factor(s) inducing apoptosis on Madin-Darby canine kidney (MDCK) cells. In this study, plasma HGF levels and HGF tissue distribution were investigated in rats with experimental acute pancreatitis, and the effects of HGF on the cytotoxic activity and apoptosis-inducing activity of PAAF also were examined. Plasma HGF levels were elevated in rats with two experimental pancreatitis models of different grades of severity. The degree of its elevation was correlated with the severity and the organ dysfunctions. In rats with severe pancreatitis, HGF protein and messenger RNA (mRNA) levels significantly increased in liver, kidney, and lung, which were injured organs. When anti-HGF neutralizing antibody was administered in severe pancreatitis, liver dysfunction worsened, and apoptotic cells increased in kidney. Recombinant HGF inhibited the cytocidal activity of PAAF on MDCK cells in a dose-dependent manner. Moreover, recombinant HGF prevented the apoptotic cell death (DNA fragmentation, nuclear fragmentation, and caspase-3 activation) induced by PAAF. These results suggest that HGF is produced in injured organs and may function as an organotrophic and antiapoptotic factor against the organ injuries in acute pancreatitis.
Ueda
T
T
The First Department of Surgery, Kobe University School of Medicine, Japan.
Takeyama
Y
Y
Hori
Y
Y
Shinkai
M
M
Takase
K
K
Goshima
M
M
Yamamoto
M
M
Kuroda
Y
Y
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D002460:Cell Line; D002108:Ceruletide / Q000633:toxicity; D053938:DNA Fragmentation; D003840:Deoxycholic Acid / Q000633:toxicity; D004285:Dogs; D004487:Edema / Q000139:chemically induced / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000378:metabolism*; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism / Q000473:pathology
D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D003840:Deoxycholic Acid; D017228:Hepatocyte Growth Factor; D002108:Ceruletide; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases