Nafamostat mesilate (NM), a protease inhibitor, possesses a cytoprotective
effect and inhibits the activation of complement. The present study investi
gated whether NM has any protective effect against injury of porcine hepato
cytes by human plasma in a bioartificial liver support system. Porcine hepa
tocytes were harvested and seeded at a density of 2 x 10(5) cells on a 35-m
m collagen-coated plate in Dulbecco's modified Eagle's medium (DMEM) with 1
0% fetal calf serum. Twenty-four hours later, the medium was replaced with
human plasma with three concentrations of NM between 3.8 x 10(-5) and 3.8 x
10(-4) M and then cultured for 6 h. The viability of porcine hepatocytes,
lactate dehydrogenase (LDH) levels, lidocaine clearance, porcine albumin pr
oduction, and changes in complement (C3) levels were measured. The viabilit
y of porcine hepatocytes in human plasma decreased significantly to 37.7 +/
- 11.4% of that in DMEM. NM improved the viability of the hepatocytes, lowe
red the levels of LDH, and increased lidocaine clearance and albumin produc
tion in a concentration-dependent manner. The concentrations of C3, the mar
ker of xenogeneic reactions, did not change significantly, indicating that
no hyperacute xenogeneic reaction occurred in our series. Together, our res
ults suggested that NM exerts favorable effects on porcine hepatocytes in h
uman plasma through direct effect such as prevention of protease activity i
n the plasma membrane of porcine hepatocytes rather than inhibition of comp
lement-dependent immunoreactions.