Granulocyte colony-stimulating factor reduces biliary fibrosis and ductular reaction in a mouse model of chronic cholestasis

Background:Biliary atresia is a rare congenital bile duct disease that is the leading cause of liver fibrosis in neonates.Granulocyte colony-stimulating factor(GCSF)is a potential therapy for hepatocellular diseases,but data on GCSF for cholestatic conditions remain limited.Materials and methods:The current study examines the role of GCSF in improving bile duct obstruction in mice.Two doses were administered:10.0 mg/kg/day and 61.5 mg/kg/day,which is the animal equivalent dose of 5.0 mg/kg in humans.Seven days(D7)after bile duct ligation(BDL),Swiss mice were treated with phosphate buffered saline or GCSF for 5 days.The intrahepatic adaptive response of BDL mice was evaluated on postsurgical days D12,D19,and D26.Results:Treatment with 61.5 mg/kg of GCSF resulted in a significant increase in circulating leukocytes and neutrophils on D12.Amelioration of liver injury,as shown by reduced aspartate aminotransferase levels,increased albumin levels and survival rate,as well as reduced intrahepatic inflammation and hepatic myeloperoxidase expression,downregulated ductular proliferation,periportal fibroblast activation,and fibrosis,enhanced expressions of hepatocyte growth factor,peroxisome proliferator-activated receptoralpha,and ki67,and suppressed expression of cleaved caspase-3 protein,was noted after treatment with 61.5 mg/kg of GCSF.Additionally,GCSF treatment was associated with an increased number of intrahepatic cd3-Sca1tc-Kitt bone marrow cells.

毫无进展:循证医学所界定的有急性肠穿孔征象的极低出生体重儿的手术时机和术式

Objective: Gut disruption in very low birth weight follows 1 of 3 clinical pathways: isolated perforation with sudden free air,metabolic derangement (MD) complicated by appearance of free air,or progressive metabolic deterioration without evidence of free air. To refine evidence-based indications for peritoneal drainage (PD) vs laparotomy (LAP),we hypothesized that MD acuity is the determinant of outcome and should dictate choice of PD or LAP. Methods: Very low-birth-weight infants referred for surgical care because of free intraperitoneal air or MD associated with signs of enteritis were evaluated by univariate or multivariate logistic regression to investigate the effect on mortality of MD and initial surgical care (LAP vs PD). Metabolic derangement was scaled by assigning 1 point each for thrombocytopenia,metabolic acidosis,neutropenia,left shift of segmented neutrophils,hyponatremia,bacteremia,or hypotension. Laparotomy and PD were stratified by MD acuity,and odds of mortality were calculated for each surgical option. Results: From October 1991 to December 2003,65 very low-birth-weight infants with suspected gut disruption were referred for surgical care. Peritoneal drainage and LAP infants had similar birth weight and gastrointestinal age,neither of which predicted edmortality. Despite a higher incidence of isolated perforation with sudden free air in PD infants,the incidence of MD and overall mortality were similar for PD and LAP. Multivariate logistic regression demonstrated MD to be the best predictor of mortality (odds ratio [OR],4.76; confidence interval [CI],1.41-16.13,P = 0.012),which significantly increased with interval between diagnosis to surgical intervention (P < 0.05). Infants with MD receiving PD had a 4-fold increase in mortality (OR,4.43; CI,1.37-14.29; P = 0.0126). Conversely,those withoutMD and sudden free air who underwent LAP had a 3-fold increase in mortality (OR,2.915; CI,1.107-7.692; P = 0.03.) Of 5,3 failed PD were “ rescued” by LAP. Conclusions: The dramatic difference in mortality odds based on surgical option in the presence of MD defines the critical importance of a thorough assessment of physiological status to exclude MD. Absence of MD warrants consideration for PD,especially for sudden intraperitoneal free air. Overwhelming MD may limit options to PD; however,salvage of 3 of 5 infants with failed PD demonstrates the value of LAP,whenever possible,for infants with MD.

Autophagy modulates physiologic and adaptive response in the liver

Autophagy is a physiological process that is ubiquitous and essential to the disposal or recycling of damaged cellular organelles and misfolded proteins to maintain organ homeostasis and survival.Its importance in the regulation of liver function in normal and pathological conditions is increasingly recognized.This review summarizes how autophagy regulates epithelial cell-and non-epithelial cellspecific function in the liver and how it differentially participates in hepatic homeostasis,hepatic injury response to stress-induced liver damage such as cholestasis,sepsis,non-alcoholic and alcohol-associated liver disease,viral hepatitis,hepatic fibrosis,hepatocellular and cholangiocellular carcinoma,and aging.Autophagy-based interventional studies for liver diseases that are currently registered in clinicatrials.gov are summarized.Given the broad and multidirectional autophagy response in the liver,a more refined understanding of the liver cell-specific autophagy activities in a context-dependent manner is necessary。