SINUSOIDAL INTERCELLULAR-ADHESION MOLECULE-1 UP-REGULATION PRECEDES THE ACCUMULATION OF LEUKOCYTE FUNCTION ANTIGEN-1-POSITIVE CELLS AND TISSUE NECROSIS IN A MODEL OF CARBONTETRACHLORIDE-INDUCED ACUTE RAT-LIVERINJURY

The mechanisms leading to the infiltration of inflammatory cells into the liver and to liver cell necrosis remain undefined. To elucidate th is process, the present work analyzes the kinetics of the expression o f intercellular adhesion molecule-1 (ICAM-1) and the accumulation of i nflammatory leukocyte function antigen-1 (LFA-l)-positive cells in rel ation to the appearance of hepatocellular necrosis in the model of acu te carbontetrachloride (CCl4)-induced liver injury. ICAM-1- and LFA-1- immunoreactivity was analyzed in normal livers and in livers obtained 3, 6, 9, 12, 18, 24, 48, and 72 hours after CCl4-administration, as we ll as in liver cells isolated 3, 6, 9, 12, 18, and 24 hours after CCl4 -administration, Total RNA extracted from livers and cells was used fo r Northern blot analysis. ICAM-1-positivity, which was detected along the sinusoids in normal rat livers, increased 3 to 6 hours after CCl4- administration and finally accumulated in the necrotic areas (24 to 48 hours post-administration). ICAM-1 steady-state mRNA levels in liver tissue increased 3 to 6 hours after CCl4-treatment and returned to nor mal levels at 48 hours after treatment. Increased amounts of ICAM-1-sp ecific transcripts could be observed in isolated sinusoidal endothelia l cells and in hepatocytes as early as 3 to 6 hours after CCl4-adminis tration, In normal rat livers, a few LFA-l-immunoreactive cells were p resent around the vessel walls. Starting 12 hours after CCl4-administr ation, the number of LFA-1-immmunoreactive cells increased around the vessel walls and along the sinusoids, accumulating later in the necrot ic areas. In accordance, the number of mononuclear phagocytes isolated from the liver increased 12 hours after CCl4-treatment. These data de monstrate an early up-regulation of ICAM-1 in liver cells and the accu mulation of LFA-l-expressing cells prior to the development of necroti c areas. The up-regulation of ICAM-1 and accumulation of inflammatory cells seem to be critical for the induction of CCl4-induced hepatotoxi city.