Objective This study determined the mechanism used by neutrophils (PMN
s) to induce hepatocellular injury Summary Background Data Neutrophils
have been shown to be potent mediators of cell and tissue injury and
have been hypothesized to contribute to the hepatic injury that occurs
after trauma and infection. Oxygen radical scavengers protect the liv
er in vivo from inflammatory injury and it has been suggested that PMN
s are the source of these toxic oxygen radicals. The specific mechanis
m used by PMNs to produce hepatocellular damage, however, has not been
determined Methods Neutrophils were cultured in vitro with hepatocyte
s (HCs) and stimulated with phorbol 12-myristate 13-acetate (PMA) to i
nduce HC injury in the presence of oxygen radical scavengers and prote
ase inhibitors. Results PMA induced a PMN-mediated HC injury that was
dependent on the number of PMNs present and the concentration of PMA.
Protease inhibitors reduced the extent of HC injury, while oxygen radi
cal scavengers had no effect. Hydrogen peroxide, directly applied, was
able to injure HCs, but only at concentrations greater than those tha
t could be produced by PMA-stimulated PMNs Conclusions PMNs are cytoto
xic to cultured HCs, predominantly due to the release of proteolytic e
nzymes, while HCs appear relatively resistant to oxidative injury, Inv
olvement of neutrophil toxic oxygen radicals in hepatic damage in vivo
may require impairment of HC antioxidant defenses or may involve inju
ry to nonparenchymal liver cells with secondary effects on HCs.