The role of a protease inhibitor against hepatectomy.
OBJECTIVE
Nafamostat Mesilate (NM) is a synthetic serine protease inhibitor that is capable of inhibiting the various coagulation factors. To determine whether NM may also be useful in attenuating operative invasiveness, we investigated the effects of perioperative administration of NM on postoperative serum levels of proinflammatory cytokine IL-6 and hepatocyte growth factor (HGF).


METHODS
Thirty patients undergoing hepatectomy with hepatocellular carcinoma, biliary carcinoma and metastatic colorectal cancer were enrolled in this study. These patients were separated into two groups; high invasive group (resected liver volume: 1000cm3 <) and less invasive group (resected liver volume: 1000cm3 >). The high invasive group of 11 patients received perioperative administration of NM (Group NM), while the less invasive group of 19 patients did not (Group C). Serum levels of IL-6, HGF and soluble IL-6 receptor (sIL-6R) were simultaneously measured on preoperative and postoperative day ('day 0', 'day 7').


RESULTS
Serum IL-6 levels on day 0 were significantly elevated and returned to preoperative levels on day 7 in both groups, and the serum IL-6 level in Group NM on day 0 was significantly lower than that in Group C on day 0. Serum HGF levels on day 0 and day 7 were significantly higher in Group NM than those in Group C. Compared with healthy control subjects, the higher serum level of HGF on the preoperative day in all patients was attributable to tumor-burden. The sIL-6R levels on day 0 decreased in both groups, and their levels in Group NM were significantly lower than those in Group C, suggesting that increased synthesis of IL-6/sIL-6R complex which could accelerate liver regeneration.


CONCLUSIONS
These results suggested that perioperative administration of NM may attenuate surgical stress by decreasing production of proinflammatory cytokine IL-6, and may accelerate liver regeneration through stimulation with the IL-6/sIL-6R complex and possible involvement of increased production of HGF.
Gotohda
Naoto
N
Department of Surgery, National Cancer Center Hospital East, Kashiwa, Japan. ngotohda@east.ncc.go.jp
Iwagaki
Hiromi
H
Ozaki
Michitaka
M
Konishi
Masaru
M
Nakagohri
Toshio
T
Takahashi
Shinichiro
S
Yagi
Takahito
T
Kinoshita
Taira
T
Tanaka
Noriaki
N
D000368:Aged; D001550:Benzamidines; D001661:Biliary Tract Neoplasms / Q000097:blood* / Q000601:surgery*; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000601:surgery*; D005260:Female; D006146:Guanidines / Q000627:therapeutic use*; D006498:Hepatectomy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000097:blood*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D008113:Liver Neoplasms / Q000097:blood* / Q000601:surgery*; D008297:Male; D011183:Postoperative Complications / Q000517:prevention & control; D011480:Protease Inhibitors / Q000627:therapeutic use*
D001550:Benzamidines; D006146:Guanidines; D015850:Interleukin-6; D011480:Protease Inhibitors; D017228:Hepatocyte Growth Factor; C032855:nafamostat