MACROPHAGE AND HEPATIC STELLATE CELL RESPONSES DURING EXPERIMENTAL HEPATOCARCINOGENESIS

The aim of the study was to assess the monocyte/macrophage and hepatic stellate cell responses during experimental diethylnitrosamine (DEN)- induced hepatocarcinogenesis. Diethylnitrosamine (50 mg/L) was adminis tered to 39 rats for 10 weeks; liver tissue was obtained at weeks 10, 16 and 19. In this model, necroinflammatory damage occurs during the p eriod of DEN administration but thereafter subsides; dysplastic nodule s and carcinomas subsequently develop. Monocytes/macrophages were dete cted immunohistochemically using ED1 and ED2 monoclonal antibodies; he patic stellate cells (HSC) were detected using antibodies to alpha-smo oth muscle actin (alpha-SMA) (activated HSC) and glial fibrillary acid ic protein (GFAP). Parenchymal ED1- and ED2-positive monocytes/macroph ages and alpha-SMA-positive HSC increased at week 10 when there was on going DEN-induced necroinflammatory activity. ED1- and ED2-positive ce lls were also prominent al weeks 16 and 19, particularly around the pe riphery of dysplastic and carcinomatous nodules, with occasional macro phages between dysplastic hepatocytes. alpha-SMA-positive HSC were pre sent within sinusoids between dysplastic cells and were more abundant at weeks 16 and 19 than in control or week 10 animals. Activated HSC w ere prominent in fibrous septa around and within dysplastic and carcin omatous nodules at weeks 16 and 19. In contrast, GFAP-positive HSC did not accumulate in developing septa or within dysplastic and carcinoma tous nodules. We have demonstrated changes in the monocyte/macrophage and HSC populations during the development of hepatocellular dysplasia and carcinoma at time points when there is little necroinflammatory a ctivity; this may therefore represent a host response to hepatocyte dy splasia. The HSC activation may be mediated, in part, by monocyte/macr ophage-derived factors, but we speculate that it may also result from direct stimulation by factors released from dysplastic hepatocytes.