Microvascular consequences of Kupffer cell modulation in rat liver fibrogenesis.
The process of Ito cell activation, which is thought to be the central pathogenic mechanism in liver fibrogenesis, may involve distinct interactions with Kupffer cells (KCs) mediated by various cytokines and growth factors. The aim of this study was to determine whether targeting KC function using gadolinium chloride (GdCl(3)) interferes with the manifestation of carbon tetrachloride (CCl(4))-induced hepatic fibrosis, placing special emphasis on the process of microvascular remodelling. Using in vivo fluorescence microscopy, characteristic microvascular features of CCl(4)-induced liver fibrosis, progressively observed within the 8-week period of toxin exposure, were the significant reduction in sinusoidal density; the increase of venular vascular space; the perivenular accumulation of Ito cells, with concomitant collagen deposition; and the collapse of parenchymal tissue. GdCl(3) effectively attenuated sinusoidal rarefaction and delayed, but did not prevent, the process of Ito cell activation-associated collagen deposition. Strikingly, the 8-week modulation of KC function by GdCl(3) exhibited sustained hepatocellular fatty vacuolation with organ weight increase, liver enzyme release, and bile flow reduction. Thus, GdCl(3) treatment attenuates the hepatic microvascular response, but favours fatty change and only delays the development of liver fibrosis following CCl(4)-exposure.
Vollmar
B
B
Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany. exbvol@med-rz.uni-sb.de
Siegmund
S
S
Richter
S
S
Menger
M D
MD
D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002251:Carbon Tetrachloride; D005682:Gadolinium / Q000494:pharmacology*; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000187:drug effects / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D008856:Microscopy, Fluorescence; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D005682:Gadolinium; D002251:Carbon Tetrachloride; C038958:gadolinium chloride