Kupffer cell inactivation delays repair in a rat model of reversible biliary obstruction

Background. During cholestatic liver injury, Kupffer cells (KC) and activat ed macrophages modulate cell proliferation and subsequent matrix deposition . The role of KC in the restoration of cell architecture and matrix metabol ism during repair following chronic cholestatic liver injury is unknown. Materials and methods. To determine the effect of KC inactivation, adult ma le Sprague-Dawley rats underwent bile duct suspension (BDS) for 5 days foll owed by reversal of the obstruction. Saline (control) and gadolinium chlori de (10 mg/kg) were administered 1 day prior to BDS and 1 day prior to rever sal, to inactivate KC during both injury and repair. Serum bilirubin and qu antitative cell morphometry were compared to verify the reversibility of th e model. Collagen content of the liver was measured in trichrome-stained pa raffin sections using NIH imaging software. Results. Reversibility of the obstruction was verified by normalization of direct serum bilirubin, which peaked at 8.42 +/- 0.76 mg/dL following 5 day s of BDS and returned to sham-operated levels 2 days after reversal, 0.36 /- 0.15 mg/dL. Hematoxylin and eosin (H&E)-stained paraffin-embedded liver sections from gadolinium-treated animals at 4 and 7 days after reversal exh ibited persistent bile duct proliferation, matrix deposition, and inflammat ion. Gadolinium-treated animals had altered collagen metabolism compared to saline controls. Whereas the collagen content in the saline group slowly r eturned to sham-operated levels over time, the treatment group demonstrated progressive accumulation of collagen during repair which was statistically significant at 7 days following reversal (8.79%/mm(2) +/- 2.17 in gadolini um group vs 2.33%/mm(2) +/- 0.34 in saline group, P = 0.0003). Conclusions. These results demonstrate that inactivation of resident hepati c macrophages during liver repair impairs collagen metabolism, inhibits the resolution of fibrosis, and allows the persistence of inflammatory cell in filtrates in the portal areas. This is the first evidence of profibrogenic responses in the absence of an intact KC compartment during repair after ch olestatic injury. (C) 2000 Academic Press.