transforming-growth-factor-beta and Biliary-Tract-Diseases

Persistent exposure of biliary epithelial cells (i.e., cholangiocytes) to diverse factors such as disordered immunity, genetic alterations, ischemia, toxic compounds and/or infectious agents leads to a chronic portal inflammatory response which eventually progresses to biliary fibrosis. This stage is characterized by increased production and deposition of scar-forming extracellular matrix proteins (ECM), in particular fibrillar collagen types I and III, but including other ECM constituents such as elastin and fibrillin-1, both components of elastic fibers. The major cellular mediators responsible for collagen deposition are activated hepatic stellate cells (HSCs) and to a lesser extent, portal myofibroblasts, which are activated by soluble inflammatory mediators (i.e., cytokines, growth factors) and extracellular matrix components. Unless the underlying cause of biliary injury can be effectively treated, these processes may ultimately lead to decompensated cirrhosis and can also provide ideal microenvironments for the development and growth of primary tumors. Recent evidence indicates that fibrosis is a dynamic and potentially reversible process. As the curative options for most chronic biliary diseases remain limited to transplantation, there is an urgent need to clarify the molecular pathways involved in the development of biliary fibrosis and identify new therapeutic targets. In this review we describe the cellular and molecular regulators that orchestrate the cholangiocyte /myofibroblast cross-talk and identify the signaling processes that are most promising for therapeutic targeting.

Topics: Animals; Biliary Tract Diseases; Epithelial Cells; Extracellular Matrix; Fibrosis; Humans; Molecular Targeted Therapy; Proto-Oncogene Proteins c-sis; Signal Transduction; Transforming Growth Factor beta

The mammalian biliary system, consisting of the intrahepatic and extrahepatic bile ducts, is responsible for transporting bile from the liver to the intestine. Bile duct dysfunction, as is seen in some congenital biliary diseases such as Alagille syndrome and biliary atresia, can lead to the accumulation of bile in the liver, preventing the excretion of detoxification products and ultimately leading to liver damage. Bile duct formation requires coordinated cell-cell interactions, resulting in the regulation of cell differentiation and morphogenesis. Multiple signaling molecules and transcription factors have been identified as important regulators of bile duct development. This review summarizes recent progress in the field. Insights gained from studies of the molecular mechanisms of bile duct development have the potential to reveal novel mechanisms of differentiation and morphogenesis in addition to potential targets for therapy of bile duct disorders.

Topics: Animals; beta Catenin; Bile Ducts, Extrahepatic; Bile Ducts, Intrahepatic; Biliary Tract Diseases; Cell Differentiation; Gene Expression Regulation, Developmental; Hepatocytes; Humans; MicroRNAs; Morphogenesis; Receptors, Notch; Signal Transduction; Transforming Growth Factor beta; Wnt Proteins

Pathogen-associated biliary fibrosis (PABF) is a type of liver fibrosis characterized by injuries of cholangiocytes and extra cellular matrix (ECM) deposition around bile ducts caused by various bacteria, fungi, virus and parasites. Recent studies show that TLR4 plays an important role in several other types of liver fibrosis, but the mechanism of TLR4 in PABF is yet really unclear. In the present study, a PABF mouse model was established by a trematode infection-Clonorchis sinensis which dwells in the bile ducts and causes severe biliary fibrosis of mice. The results showed that the levels of collagen depositions, α-SMA and hydroxyproline (Hyp) contents in TLR4

Topics: Animals; Biliary Tract Diseases; Biomarkers; Clonorchiasis; Clonorchis sinensis; Disease Models, Animal; Fibrosis; Mice; Mice, Transgenic; Mutation; Poly(A)-Binding Proteins; Signal Transduction; Toll-Like Receptor 4; Transforming Growth Factor beta

To determine characteristics of a cytokine status in chronic pancreatitis (CP) depending on etiological factor, stage of the disease, complications, therapy. Material and methods. 72 patients had chronic alcoholic pancreatitis (CAP), 38 patients--chronic biliary pancreatitis (CBP). Control group consisted of 20 healthy subjects.. At early stages and height of CAP exacerbation, concentrations of IL-1beta, IL-6, IL-8, TNF-gamma and TNFalpha were elevated (951.1 +/- 104.2 pg/ml; 172.8 +/- 24.3 pg/ml; 432.6 +/- 68.5 pg/ml; 823.3 +/- 97.5 pg/ml; 158.7 +/- 19.6 pg/ml, respectively). Regenerative processes in CP were accompanied with IL-4 elevation to 614.9 +/- 64.6 pg/ml. In CAP without complications and with them the levels of cytokines differed significantly. The level of TGF-beta1 stimulating development of fibrosis was in CAP patients 627.8 +/- 92.2 pg/ml, in CAP patients with complications--796.8 +/- 102.5, in the controls--40.2 +/- 4.6 pg/ml (p < 0.05). In early stages of CBP exacerbation, IL-1beta rose to 527.2 +/- 62.7 pg/ml, IL-6--to 80.9 +/- 11.4 pg/ml, IL-8--to 290.4 +/- 46.8 pg/ml, INF-gamma to 853.3 +/- 91.6 pg/ml; TNF-alpha--to 79.7 +/- 8.3 pg/ml, TGF-beta1--534.1 +/- 78.4 pg/ml. With attenuation of acute syndromes and development ofregeneration, levels of IL-4 went up (226.7 +/- 32.4 pg/ml).. CP is accompanied by increase in cytokine contents depending on the etiological factor, variants of course, stage, presence of complications.

Topics: Adult; Biliary Tract Diseases; Biomarkers; Cytokines; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Interferon-gamma; Interleukin-1; Interleukin-4; Interleukin-6; Interleukin-8; Male; Middle Aged; Pancreatitis, Alcoholic; Pancreatitis, Chronic; Prognosis; Severity of Illness Index; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The expression of several growth factors and K-ras gene mutation in bile were studied to better understand the pathogenesis and improve early diagnosis of bile duct cancers. Bile samples were collected from 12 cholangiocarcinomas (CLC), 10 ampullary cancers (APC), 3 gallbladder cancers (GBC), 7 pancreatic cancers (PNC), 9 biliary tract infection (BTI), 8 biliary stone disease (ST), and 5 normal controls (NC). The highest mean value of TGF-beta in bile was in patients with BTI; the mean levels of bFGF and PDGF were highest in CLC, and patients with APC and CLC had higher expression of HER2/Neu than other groups. In bile, a K-ras gene codon 12 mutation was found in 5 of 6 (83%) cases of CLC by the PCR-RFLP method. The results suggest overexpression of bFGF, PDGF, and HER2/Neu and the presence of K-ras mutation are important for carcinogenesis of bile duct cancers, and detection of the above abnormalities in bile is helpful for early diagnosis.

Topics: Ampulla of Vater; Bile; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biliary Tract Diseases; Biliary Tract Neoplasms; Biomarkers; Biomarkers, Tumor; Cholangiocarcinoma; Cholelithiasis; Common Bile Duct Neoplasms; Enzyme-Linked Immunosorbent Assay; Gallbladder Neoplasms; Humans; Infections; Pancreatic Neoplasms; Platelet-Derived Growth Factor; Polymerase Chain Reaction; ras Proteins; Receptor, ErbB-2; Transforming Growth Factor beta