Reactive oxygen intermediates and eicosanoid production by Kupffer cells and infiltrated macrophages in acute and chronic liver injury induced in rats by CCl4

Objective and Design: The aim of the present study was to characterize duri ng acute and chronic liver injury induced by CCl4, macrophage phenotypes an d whether a change in reactive oxygen intermediates (ROI) and eicosanoids p roduction by Kupffer cells (KC) was observed. Material and Methods: Liver steato-necrosis and cirrhosis were induced in r ats after 3 weeks and 9 weeks of CCl4 intoxication, respectively. Monocytes and tissue macrophages were identified by immunohistochemical study using monoclonal antibodies ED-1 and tissue macrophages using the antibody ED-2. The release of ROI and eicosanoids in response to the phorbol ester TPA (pr otein kinase activator) and to the calcium ionophore A23187 was assessed in cultivated cells. Results: As compared to healthy controls, livers of rats with steato-necros is or cirrhosis exhibited a significant increase of ED-1 and ED-2 positive cells. Only KC from rats with liver steato-necrosis were found to have high er A23187, TPA + A23187 or opsonized zymosan induced ROI production than he althy controls (p < 0.01). After TPA + A23187 or opsonized zymosan stimulat ion, KC from both rats with steato-necrosis or cirrhosis produced more TxB2 and leukotrienes and less PGE2 as compared to healthy controls (p<0.05). Conclusions: These results suggest an influx of monocytes into the liver du ring acute and chronic injury induced by CCl4. Functional changes of this i nflammatory infiltrate have been demonstrated with an increase of ROI produ ction only in the early stage of liver injury whereas a rise in KC leukotri ene production and an imbalance between cytoprotective and cytotoxic prosta noids were observed at all stages of liver disease.