Regulation of hepatic blood flow:The hepatic arterial buffer response revisited

The interest in the liver dates back to ancient times when it was considered to be the seat of life processes. The liver is indeed essential to life,not only due to its complex functions in biosynthesis,metabolism and clearance,but also its dramatic role as the blood volume reservoir. Among parenchymal organs,blood flow to the liver is unique due to the dual supply from the portal vein and the hepatic artery. Knowledge of the mutual communication of both the hepatic artery and the portal vein is essential to understand hepatic physiology and pathophysiology. To distinguish the individual importance of each of these inflows in normal and abnormal states is still a challenging task and the subject of on-going research. A central mechanism that controls and allows constancy of hepatic blood flow is the hepatic arterial buffer response. The current paper reviews the relevance of this intimate hepatic blood flow regulatory system in health and disease. We exclusively focus on the endogenous interrelationship between the hepatic arterial and portal venous inflow circuits in liver resection and transplantation,as well as inflammatory and chronic liver diseases. We do not consider the hepatic microvascular anatomy,as this has been the subject of another recent review.

Impact of hyperglycemia on autoimmune pancreatitis and regulatory T-cells

AIM To evaluate the influence of hyperglycemia on the progression of autoimmune pancreatitis.METHODS We induced hyperglycemia by repetitive intraperitoneal(ip) injection of 50 mg/kg streptozotocin in MRL/Mp J mice, which develop autoimmune pancreatitis due to a genetic predisposition. We compared the extent of inflammation(histological score, CD3^+ lymphocytes, CD8^+ T-cells, CD4^+ T-cells, Foxp3^+ T-helper cells) in the pancreas of hyperglycemic and normoglycemic mice. We also analyzed the number of leukocytes, lymphocytes, granulocytes and monocytes in the blood. In addition, we determined the percentage of CD3^+ lymphocytes, CD8^+ T-cells, CD4^+ T-cells, Foxp3^+ T-helper cells, Foxp3^+ CD25^+ T-helper and Foxp3^+T-helper cells in the spleen by flow cytometry.RESULTS Treatment with streptozotocin caused a strong induction of hyperglycemia and a reduction in body weight(P < 0.001). Severe hyperglycemia did not, however, lead to an aggravation, but rather to a slight attenuation of autoimmune pancreatitis. In the pancreas, both the histological score of the pancreas as well as the number of CD3+ lymphocytes(P < 0.053) were decreased by hyperglycemia. No major changes in the percentage of CD8^+ T-cells, CD4^+ T-cells, Foxp3^+ T-helper cells were observed between hyperglycemic and normoglycemic mice. Hyperglycemia increased the numbers of leukocytes(P < 0.001), lymphocytes(P = 0.016), granulocytes and monocytes(P = 0.001) in the blood. Hyperglycemia also moderately reduced the percentage of CD3^+ lymphocytes(P = 0.057), significantly increased the percentage of Foxp3^+ T-helper cells(P = 0.018) and Foxp3^+ CD25^+ T-helper cells(P = 0.021) and reduced the percentage of Foxp3^+T-helper cells(P = 0.034) in the spleen. CONCLUSION Hyperglycemia does not aggravate but moderately attenuates autoimmune pancreatitis, possibly by increasing the percentage of regulatory T-cells in the spleen.

Limited potential of resolvin D1 in treatment of cholestatic liver fibrosis

Background:Several studies suggest a role for EPA-and DHA-derived pro-resolving mediators like resolvins in reversing metabolic and inflammatory disturbances seen in various chronic diseases.Here,we investigated the effects of resolvin D1(RvD1)on bile duct ligation(BDL)-induced cholestatic liver injury.Methods:Mice were treated daily with RvD1 or 0.1%ethanol(control)from the day of BDL until the final observation time points.Blood and liver tissue were collected 2,5 and 14 days after BDL for different analyses.Results:RvD1 treatment of mice had no impact on the extent of cholestatic liver injury upon BDL,neither in the acute phase nor in the progressive state of liver fibrosis.Although RvD1 treatment resulted in a significantly reduced activity of hepatic stellate cells as well as reduced deposition of extracellular matrix 2 days after BDL,mice were not protected from inflammation and further fibrosis progression.Conclusions:These data indicate that RvD1 has a limited therapeutic potential to treat cholestatic liver diseases,as it has no significant impact on regression of hepatic necroinflammation and fibrotic changes in bile duct-ligated mice.

Endogenously increased n-3 PUFA levels in fat-1 transgenic mice do not protect from non-alcoholic steatohepatitis

Background:Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver diseaseworldwide,ranging from simple steatosis to non-alcoholic steatohepatitis(NASH)and fibrosis.Possiblereasons for the NAFLD epidemic in industrialized countries are the high intake of pro-inflammatory n-6polyunsaturated fatty acids(n-6 PUFAs)and low consumption of healthy n-3 PUFAs.Due to their antiinflammatoryproperties,n-3 PUFAs may have the potential to alleviate chronic liver disease.Herein,weexamined the therapeutic effect of increased n-3 PUFA tissue levels in fat-1 transgenic mice on progressiveNASH.Methods:Disease was induced in mice by streptozotocin and high fat diet(STZ/HFD)resulting in NASH.NAFLD in 6 and 8 weeks old wild type and fat-1 transgenic STZ/HFD treated mice was analyzed.Unlikeall other mammals,fat-1 transgenic mice ubiquitously express an n-3 fatty acid desaturase,which converts n-6to n-3 PUFAs,leading to increased n-3 and decreased n-6 PUFA tissue contents.Results:Liver damage,NAFLD activity score(NAS),hepatic lipid accumulation and inflammation weresignificantly reduced in fat-1 transgenic STZ/HFD treated mice in the early(6 weeks)but not late(8 weeks)phase of NASH.Simultaneously,mRNA expression of genes involved in fatty acid uptake and storage(Cd36and Plin3,respectively)was significantly down-regulated in 6 week old but not 8 week old fat-1 transgenicSTZ/HFD treated mice.Conclusions:Endogenously elevated n-3 PUFA levels in fat-1 transgenic mice transiently delay the onsetof STZ/HFD induced NASH but failed to efficiently protect from NASH development.