Dexamethasone alters the hepatic inflammatory cellular profile without changes in matrix degradation during liver repair following biliary decompression.
BACKGROUND
Biliary atresia is characterized by extrahepatic bile duct obliteration along with persistent intrahepatic portal inflammation. Steroids are standard in the treatment of cholangitis following the Kasai portoenterostomy, and were advocated for continued suppression of the ongoing immunologic attack against intrahepatic ducts. Recent reports, however, have failed to demonstrate an improved patient outcome or difference in the need for liver transplant in postoperative patients treated with a variety of steroid regimes compared with historic controls. In the wake of progressive liver disease despite biliary decompression, steroids are hypothesized to suppress inflammation and promote bile flow without any supporting data regarding their effect on the emerging cellular and molecular mechanisms of liver repair. We have previously shown in a reversible model of cholestatic injury that repair is mediated by macrophages, neutrophils, and specific matrix metalloproteinase activity (MMP8); we questioned whether steroids would alter these intrinsic mechanisms.


METHODS
Rats underwent biliary ductal suspension for 7 d, followed by decompression. Rats were treated with IV dexamethasone or saline at the time of decompression. Liver tissue obtained at the time of decompression or after 2 d of repair was processed for morphometric analysis, immunohistochemistry, and quantitative RT-PCR.


RESULTS
There was a dramatic effect of dexamethasone on the inflammatory component with the initiation of repair. Immunohistochemistry revealed a reduction of both ED1+ hepatic macrophages and ED2+Kupffer cells in repair compared with saline controls. Dexamethasone treatment also reduced infiltrating neutrophils by day 2. TNF-alpha expression, increased during injury in both saline and dexamethasone groups, was markedly reduced by dexamethasone during repair (day 2) whereas IL-6, IL-10, and CINC-1 remained unchanged compared with saline controls. Dexamethasone reduced both MMP8 and TIMP1 expression by day 2, whereas MMP9, 13, and 14 were unchanged compared with sham controls. Despite substantial cellular and molecular changes during repair, collagen resorption was the same in both groups


CONCLUSIONS
Dexamethasone has clear effects on both the hepatic macrophage populations and infiltrating neutrophils following biliary decompression. Altered MMP and TIMP gene expression might suggest that steroids have the potential to modify matrix metabolism during repair. Nevertheless, successful resorption of collagen fibrosis proceeded presumably through other MMP activating mechanisms. We conclude that steroids do not impede the rapid intrinsic repair mechanisms of matrix degradation required for successful repair.
Muratore
Christopher S
CS
Department of Surgery, Division of Pediatric Surgery and Surgical Research, Hasbro Children's Hospital and Rhode Island Hospital, The Alpert Medical School of Brown University, Providence, Rhode Island 02905, USA. Christopher_Muratore@brown.edu
Harty
Mark W
MW
Papa
Elaine F
EF
Tracy
Thomas F
TF
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001652:Bile Ducts / Q000601:surgery; D001656:Biliary Atresia / Q000503:physiopathology / Q000628:therapy*; D002779:Cholestasis / Q000503:physiopathology / Q000628:therapy; D003094:Collagen / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D019299:Decompression, Surgical; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D007728:Kupffer Cells / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D051381:Rats
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D003907:Dexamethasone; D003094:Collagen