Dexamethasone Alters the Hepatic Inflammatory Cellular Profile Without Changes in Matrix Degradation During Liver Repair Following Biliary Decompression

Abstract

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 liberally adopted advocated for continued suppression of the ongoing immunological 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 to historical 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 days 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 days (D2) 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 when compared to saline controls. Dexamethasone treatment also reduced infiltrating neutrophils by D2. TNF-α expression, increased during injury in both saline and dexamethasone groups, was markedly reduced by dexamethasone during repair (D2) whereas IL-6, IL-10 and CINC-1 remained unchanged when compared to saline controls. Dexamethasone reduced both MMP8 and TIMP1 expression by D2, whereas MMP9, 13, and 14 were unchanged when compared to sham controls. Despite substantial cellular and molecular changes during repair, collagen resorption was the same in both groups Conclusion 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.

Effects of Prednisone on Urinary Proteome and Disease Biomarkers in a Rat Model

“…The strong association between prednisone treatment and protein metabolism may also contribute to the changes in the urinary proteome. Several differential proteins identified in current study were reported to be regulated by glucocorticoids in previous studies, such as the serine protease inhibitor A3N, 12 alpha-1-acid glycoprotein, 13 mMP8, 14 growth hormone receptor 15 insulin-like growth factor-binding protein 3 16 and acyl-CoA-binding protein, 17 suggesting the reliability of the proteomics results. Moreover, two differentially expressed proteins (Haptoglobin and Neutrophil collagenase) in our study were further validated by Western Blot.…”

Glucocorticoid Modulates High-Mobility Group Box 1 Expression and Toll-Like Receptor Activation in Obstructive Jaundice

“…Muratore et al have provided the explanation that dexamethasone can alter the hepatic inflammatory cellular profile without changes in matrix degradation during liver repair following biliary decompression [39]. Previous studies by the authors have demonstrated that glucocorticoid treatment suppresses LPSinduced chemokine expression and inflammatory cells infiltration as well as oxidative stress in cholestatic rats receiving biliary intervention [13][14][15].…”

Hepatocytes buried in the cirrhotic livers of patients with biliary atresia proliferate and function in the livers of urokinase‐type plasminogen activator–NOG mice

“…In the first few weeks of life, a Kasai portoenterostomy is performed to bypass the obstructed extrahepatic bile ducts and restore the biliary flow. 3 Approximately 20% of all patients who undergo portoenterostomy during infancy survive into adulthood with their native liver. 2 , 4 In general, it is advantageous to perform portoenterostomy as early after birth as possible to optimize the chance of success.…”