Sinusoidal endothelial cells as an early target for hepatic toxicants

Recent studies demonstrate that the hepatic sinusoidal endothelial cells (SEC) are a sensitive direct target for early toxicity to acetaminophen (paracetamol, APAP) and this toxicity is exacerbated following a single and multiple week-end type alcoholic binge(s). SEC become swollen and begin to lose the ability to endocytose FITC-FSA, a ligand for the scavenger receptor, as early as 30 minutes after the administration of APAP. Gaps through the SEC appear to be formed by the destruction and/or coalescence of fenestrae and are seen as early as 2 hrs after the administration of APAP which is prior to any evidence of injury to parenchymal cells. The gaps permit red blood cells to penetrate into the Space of Disse. Subsequently, the sinusoid may collapse or disintegrate reducing blood flow. The gaps are larger and more frequent in ethanol binged animals subsequently treated with APAP. Similar gaps are seen in the early stages of hepatic venoocclusive disease. Administration of a NO donor or a MMP-2 and MMP-9 inhibitor minimizes endothelial injury and red blood cell penetration into the Space of Disse. The injury is exacerbated when an inhibitor of eNOS is administered and minimized when iNOS is inhibited suggesting a protective role for constitutive NO derived from SEC. Both NO and MMPs are known to affect the cytoskeleton of SEC which in turn affects the formation and maintenance of the fenestrae.