Hepatitis C virus (HCV)
infection is a major cause of
liver disease characterized by
inflammation, cell damage, and fibrotic reactions of hepatocytes. Apoptosis has been implicated in the pathogenesis, although it is unclear whether
proteases of the
caspase family as the central executioners of apoptosis are involved and how
caspase activation contributes to liver injury. In the present study, we measured the activation of
effector caspases in liver biopsy specimens of patients with chronic HCV
infection. The activation of
caspase-3,
caspase-7, and cleavage of
poly(ADP-ribose)polymerase (PARP), a specific
caspase substrate, were measured by immunohistochemistry and Western blot analysis by using
antibodies that selectively detect the active truncated, but not the inactive precursor forms of the
caspases and PARP. We found that
caspase activation was considerably elevated in liver lobules of HCV patients in comparison to normal controls. Interestingly, the immunoreactive cells did yet not reveal an overt apoptotic morphology. The extent of
caspase activation correlated significantly with the disease grade, i.e., necroinflammatory activity. In contrast, no correlation was observed with other
surrogate markers such as serum
transaminases and viral load. In biopsy specimens with low activity (grade 0) 7.7% of the hepatocytes revealed
caspase-3 activation, whereas 20.9% of the cells stained positively in grade 3. Thus, our results suggest that
caspase activation is involved in HCV-associated liver injury. Moreover, measurement of
caspase activity may represent a reliable marker for the early detection of liver damage, which may open up new diagnostic and therapeutic strategies in HCV
infection.