The purpose of this study was to identify the receptor responsible for endocytosis of denatured collagen from blood. The major site of clearance of this material (at least 0.5 g/day in humans) is a receptor on liver sinusoidal endothelial cells (LSECs). We have now identified an 180-kDa endocytic receptor on LSECs, peptide mass fingerprinting of which revealed it to be the mannose receptor. Challenge of mannose-receptor knockout mice and their cultured LSECs revealed significantly reduced blood clearance and a complete absence of LSEC endocytosis of denatured collagen. Organ analysis of wild-type versus knockout mice after injection of denatured collagen revealed significantly reduced liver uptake in the knockout mice. Clearance/endocytosis of ligands for other receptors in these animals was as that for wild-type mice, and denatured collagen uptake in wild-type mice was not affected by other ligands of the mannose receptor, namely mannose and mannan. Furthermore, unlike that of mannose and mannan, endocytosis of denatured collagen by the mannose receptor is calcium independent. This suggests that the binding site for denatured collagen is distinct from that for mannose/mannan. Mannose receptors on LSECs appear to have less affinity for circulating triple helical type I collagen. Conclusion: The mannose receptor is the main candidate for being the endocytic denatured collagen receptor on LSECs. (HEPATOLOGY 2007;45:1454-1461

Purpose To investigate the correlation between MRE assessed spleen stiffness and direct portal vein pressure gradient (D-HVPG) measurements in a large animal model of portal hypertension. Materials and Methods Cholestatic liver disease was established in adult canines by common bile duct ligation. A spin echo based EPI MRE sequence was used to acquire 3-D/3-axis abdominal MRE data at baseline, four weeks, and eight weeks. Liver biopsies, blood samples, and D-HVPG measurements were obtained simultaneously. Results Animals developed portal hypertension (D-HVPG: 11.0±5.1 mmHg) with only F1 fibrosis after four weeks. F3 fibrosis was confirmed after eight weeks despite no further rise in portal hypertension (D-HVPG: 11.3±3.2 mmHg). Mean stiffnesses of the spleen increased over two-fold from baseline (1.72±0.33 kPa) to four weeks (3.54±0.31 kPa), and stabilized at eight weeks (3.38±0.06 kPa) in a pattern consistent with changes in portal pressure. A positive correlation was observed between spleen stiffness and D-HVPG (r2 = 0.86, p<0.01). Conclusion These findings indicate a temporal relationship between portal hypertension and the development of liver fibrosis in a large animal model of cholestatic liver disease. The observed direct correlation between spleen stiffness and D-HVPG suggest a non-invasive MRE approach to diagnose and screen for portal hypertension.

Background: Increased intracranial pressure (ICP) worsens the outcome of acute liver failure (ALF). This study investigates the underlying pathophysiological mechanisms and evaluates the therapeutic effect of albumin dialysis in ALF with use of the Molecular Adsorbents Recirculating System without hemofiltration/dialysis (modified, M-MARS).