Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling.

Background And Aims: Cholestasis is characterized by increased total bile acid (TBA) levels, which are regulated by farnesoid X receptor (FXR)/FGF15. Patients with primary sclerosing cholangitis (PSC) typically present with inflammatory bowel disease (IBD). Mast cells (MCs) (i) express FXR and (ii) infiltrate the liver during cholestasis promoting liver fibrosis.

Mast Cells Promote Nonalcoholic Fatty Liver Disease Phenotypes and Microvesicular Steatosis in Mice Fed a Western Diet.

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) is simple steatosis but can develop into nonalcoholic steatohepatitis (NASH), characterized by liver inflammation, fibrosis, and microvesicular steatosis. Mast cells (MCs) infiltrate the liver during cholestasis and promote ductular reaction (DR), biliary senescence, and liver fibrosis. We aimed to determine the effects of MC depletion during NAFLD/NASH.

Mast Cells Induce Ductular Reaction Mimicking Liver Injury in Mice Through Mast Cell-Derived Transforming Growth Factor Beta 1 Signaling.

Background And Aims: Following liver injury, mast cells (MCs) migrate into the liver and are activated in patients with cholestasis. Inhibition of MC mediators decreases ductular reaction (DR) and liver fibrosis. Transforming growth factor beta 1 (TGF-β1) contributes to fibrosis and promotes liver disease.

Amelioration of Large Bile Duct Damage by Histamine-2 Receptor Vivo-Morpholino Treatment.

Histamine binds to one of the four G-protein-coupled receptors expressed by large cholangiocytes and increases large cholangiocyte proliferation via histamine-2 receptor (H2HR), which is increased in patients with primary sclerosing cholangitis (PSC). Ranitidine decreases liver damage in Mdr2 (ATP binding cassette subfamily B member 4 null) mice. We targeted hepatic H2HR in Mdr2 mice using vivo-morpholino.

Biliary damage and liver fibrosis are ameliorated in a novel mouse model lacking l-histidine decarboxylase/histamine signaling.

Primary sclerosing cholangitis (PSC) is characterized by biliary damage and fibrosis. Multidrug resistance-2 gene knockout (Mdr2) mice and PSC patients have increased histamine (HA) levels (synthesized by l-histidine decarboxylase, HDC) and HA receptor (HR) expression. Cholestatic HDC mice display ameliorated biliary damage and hepatic fibrosis.

Downregulation of hepatic stem cell factor by Vivo-Morpholino treatment inhibits mast cell migration and decreases biliary damage/senescence and liver fibrosis in Mdr2 mice.

Unlabelled: Primary sclerosing cholangitis (PSC) is characterized by increased mast cell (MC) infiltration, biliary damage and hepatic fibrosis. Cholangiocytes secrete stem cell factor (SCF), which is a chemoattractant for c-kit expressed on MCs. We aimed to determine if blocking SCF inhibits MC migration, biliary damage and hepatic fibrosis.

Prolonged intake of desloratadine: mesenteric lymphatic vessel dysfunction and development of obesity/metabolic syndrome.

This study aimed to establish mechanistic links between the prolonged intake of desloratadine, a common H1 receptor blocker (i.e., antihistamine), and development of obesity and metabolic syndrome.

Ursodeoxycholate inhibits mast cell activation and reverses biliary injury and fibrosis in Mdr2 mice and human primary sclerosing cholangitis.

Ursodeoxycholic acid (UDCA) is used to treat biliary disorders; and, bile acids alter mast cell (MC) histamine release. MCs infiltrate Mdr2 mice liver (model of primary sclerosing cholangitis (PSC)). MC-derived histamine increases inflammation, hepatic stellate cell (HSC) activation and fibrosis.

Blocking H1/H2 histamine receptors inhibits damage/fibrosis in Mdr2 mice and human cholangiocarcinoma tumorigenesis.

Primary sclerosing cholangitis (PSC) patients are at risk of developing cholangiocarcinoma (CCA). We have shown that (1) histamine increases biliary hyperplasia through H1/H2 histamine receptors (HRs) and (2) histamine levels increase and mast cells (MCs) infiltrate during PSC and CCA. We examined the effects of chronic treatment with H1/H2HR antagonists on PSC and CCA.

Cellular crosstalk during cholestatic liver injury.

The functions of the liver are very diverse. From detoxifying blood to storing glucose in the form of glycogen and producing bile to facilitate fat digestion, the liver is a very active and important organ. The liver is comprised of many varied cell types whose functions are equally diverse.

Knockout of l-Histidine Decarboxylase Prevents Cholangiocyte Damage and Hepatic Fibrosis in Mice Subjected to High-Fat Diet Feeding via Disrupted Histamine/Leptin Signaling.

Feeding a high-fat diet (HFD) coupled with sugar, mimicking a Western diet, causes fatty liver disease in mice. Histamine induces biliary proliferation and fibrosis and regulates leptin signaling. Wild-type (WT) and l-histidine decarboxylase (Hdc) mice were fed a control diet or an HFD coupled with a high fructose corn syrup equivalent.

Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights.

Nonalcoholic fatty liver disease (NAFLD) is a disease of increasing interest, as its prevalence is on the rise. NAFLD has been linked to metabolic syndrome, which is becoming more common due to the Western diet. Because NAFLD can lead to cirrhosis and related complications including hepatocellular carcinoma, the increasing prevalence is concerning, and medical therapy aimed at treating NAFLD is of great interest.

Recent Advances in Understanding Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive malignancy that arises from damaged epithelial cells, cholangiocytes, and possibly de-differentiated hepatocytes. CCA has a poor overall survival rate and limited therapeutic options. Based on this data, it is imperative that new diagnostic and therapeutic interventions be developed.

The emerging role of mast cells in liver disease.

The depth of our knowledge regarding mast cells has widened exponentially in the last 20 years. Once thought to be only important for allergy-mediated events, mast cells are now recognized to be important regulators of a number of pathological processes. The revelation that mast cells can influence organs, tissues, and cells has increased interest in mast cell research during liver disease.

Bile duct ligation-induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell-deficient Kit mice.

Unlabelled: Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL), increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC-deficient (Kit ) mice. Wild-type (WT) and Kit mice were subjected to sham or BDL for up to 7 days and Kit mice were injected with cultured mast cells or 1× phosphate-buffered saline (PBS) before collecting serum, liver, and cholangiocytes.

Isolation and characterization of hepatic mast cells from cholestatic rats.

Mast cells (MCs) are immune cells that release histamine and other mediators. MC number increases after bile duct ligation (BDL) and blocking mast cell-derived histamine decreases biliary proliferation. We aimed to isolate and characterize MCs from cholestatic livers.

Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice.

Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to have a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis.

Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2(-/-) mice.

Unlabelled: Hepatic fibrosis is marked by activation of hepatic stellate cells (HSCs). Cholestatic injury precedes liver fibrosis, and cholangiocytes interact with HSCs promoting fibrosis. Mast cells (MCs) infiltrate following liver injury and release histamine, increasing biliary proliferation.

Inhibition of Mast Cell-Derived Histamine Decreases Human Cholangiocarcinoma Growth and Differentiation via c-Kit/Stem Cell Factor-Dependent Signaling.

The tumor microenvironment of cholangiocarcinoma (CCA) is composed of numerous cells, including mast cells (MCs). MCs release histamine, which increases CCA progression and angiogenesis. Cholangiocytes secrete stem cell factor, which functions via the MC growth factor receptor c-Kit.

Development and functional characterization of extrahepatic cholangiocyte lines from normal rats.

Background: Since limited in vitro tools exist for evaluating the pathophysiology of extrahepatic bile ducts, we aim to develop an extrahepatic cholangiocyte culture system from normal rats.

Methods: Extrahepatic ducts were dissected from rats, cut in half length-wise and cultured on collagen-I coated plates. Transepithelial electrical resistance was measured.

Inhibition of mast cell-derived histamine secretion by cromolyn sodium treatment decreases biliary hyperplasia in cholestatic rodents.

Cholangiopathies are characterized by dysregulation of the balance between biliary growth and loss. We have shown that histamine (HA) stimulates biliary growth via autocrine mechanisms. To evaluate the paracrine effects of mast cell (MC) stabilization on biliary proliferation, sham or BDL rats were treated by IP-implanted osmotic pumps filled with saline or cromolyn sodium (24 mg/kg BW/day (inhibits MC histamine release)) for 1 week.

Vitamin D and GI cancers: shedding some light on dark diseases.

VITAMIN D SYNTHESIS AND SIGNALING AFFECTS NUMEROUS CELLULAR PROCESSES INCLUDING: proliferation, differentiation and apoptosis. It is now commonly recognized that low levels of vitamin D are associated with a greater risk of tumorigenesis. Cancers of the gastrointestinal tract are most often difficult to diagnose and treat as patients typically present with progressed disease.

Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling.

Histidine is converted to histamine by histidine decarboxylase (HDC). We have shown that cholangiocytes 1) express HDC, 2) secrete histamine, and 3) proliferate after histamine treatment via ERK1/2 signaling. In bile duct-ligated (BDL) rodents, there is enhanced biliary hyperplasia, HDC expression, and histamine secretion.

Overexpression of membrane metalloendopeptidase inhibits substance P stimulation of cholangiocarcinoma growth.

Substance P (SP) promotes cholangiocyte growth during cholestasis by activating its receptor, NK1R. SP is a proteolytic product of tachykinin (Tac1) and is deactivated by membrane metalloendopeptidase (MME). This study aimed to evaluate the functional role of SP in the regulation of cholangiocarcinoma (CCA) growth.