Internal Medicine
333 Cedar Street
Room LMP-1072
P.O. Box 208056
New Haven, CT 06520-8056
Professor
Section of Digestive Diseases
more on this physician
Transplant Hepatology, Hepatocellular Carcinoma, Biliary Tree Diseases
Epithelial Cell Biology, Pathophysiology of Diseases of the Biliary Tree, Liver Cell Therapy, Treatment of Liver Cancer
The main focus of my laboratory is the pathophysiology and therapy of diseases of the biliary tree (also called cholangiopathies). This is a large group of chronic liver diseases, congenital or acquired, that causes significant morbility and mortality in both the adult and pediatric population. The pathogenesis of biliary tree diseases is still elusive and, contrary to other areas of hepatology, effective treatment is still lacking. Liver transplantation remains the only treatment available for cases progressing to end-stage liver disease. On the other hand, many complications of liver transplantation involve the biliary tree, and biliary cells are intimately involved in liver repair and regeneration. Therefore, the basic scientific interest of the lab nicely complements the clinical interest of the group as it translates into the practice of transplant Hepatology.
Pathophysiology of cholangiopathies.
Previous work from my laboratory has contributed to the understanding
of the normal physiology of biliary cells and to the identification of
prototypic mechanisms for biliary damage for which a model human cholangiopathy
exists (Fig. 1). Among them, the lab is now addressing the pathophysiology
and treatment of Cystic Fibrosis cholangiopathy, polycystic liver disease
and Alagille syndrome.
Cystic Fibrosis (CF) that alters the ability of the biliary epithelium to secrete Cl - through CFTR, and may leads to sclerosing cholangitis and biliary cirrhosis. We have shown that CFTR loss of function affects bicarbonate transport in biliary duct cells, which in certain circumstances this block can be overcome by purinergic signaling, by aminoglicoside antibiotics and by sulphonylureas. More recent on-going work focuses: a) on the effects of ursodeoxycholic acid (UDCA) on biliary epithelia from CF mice models, and b) the use of cell transplantation strategies to treat genetic diseases of the biliary tree.
Polycystic diseasesof the liver (PLD) are a group of extremely interesting developmental genetic cholangiopathies. In these diseases altered function of ciliary proteins causes dramatic changes in cholangiocyte biology, from altered development resulting in "ductal plate malformations, to altered secretory response to sheer stress, to hyperproliferation, and stimulation of excessive portal fibrogenesis. We have described an increased expression of angiogenic factors in the biliary and cystic epithelium of patients with ADPKD and with Caroli Disease (Fig.2). Angiopoietin-1 and VEGF overexpression may have an autocrine stimulatory effect on cystic cholangiocyte growth. In collaboration with Dr. Somlo and the Yale ADPKD Center and thanks to a novel technique enabling the propagation of primary cholangiocyte cultures from wild-type and PLD transgenic mice, we are planing to explore the intracellular signaling pathways involved in autocrine angiogenic signaling in PLD cystic epithelium and to evaluate the potential inhibitory effect of VEGF signaling blockade on cyst growth in vivo using ADPKD mice.
Alagille Syndrome, a developmental disease of the biliary tree caused by an altered Jaggeded-1/Notch-2 signaling. The patient with Alagille syndrome has severe ductopenia, is jaundiced, and is severely itching, but rarely develops terminal liver diseases and liver fibrosis is negligible. Studies are ongoing to clarify the role of Notch in liver repair and development. In Alagille syndrome there is important cholestasis in the absence of ductular reaction and with an accumulation of intermediate hepatocytes, our hypothesis is that Notch signaling is needed for progenitor cell progression to a biliary phenotype.
Another interest of my group is to understand the role of "activated" biliary cells and liver progenitor cells in liver repair mechanisms. The hypothesis is that, although both mature hepatocytes and biliary cells are able of substantial proliferation, this is restricted to experimental conditions and to rare human conditions, while in most cases of chronic liver diseases, liver repair requires the activation of a population of liver "progenitor cells" closely related to the epithelial cells of the terminal cholangioles. Specific hystochemical markers and a rigorous morphometric approach progenitor cells reaction are used to study with in a number of prototypic diseases.
Finally, the group is interested on hepatocellular carcinoma (HCC) therapy. HCC is one of the most frequent malignant neoplasms worldwide and a leading cause of mortality in the western cirrhotic population. HCC is also an important indication for liver transplantation. Many questions are still open concerning the optimal treatment of HCC. We are studying a prospectively followed up cohort of cirrhotic patients with incident HCC treated according to the BCLC staging system. Studies are planned to implement strategies to reduce recurrence in this population.
The group has a number of international collaborations. Most relevant among them are the ones with the CeLiveR ( Hospital of Bergamo), the University of Milano-Bicocca (with which a joint master program in Transplant Hepatology is run), and the University of Padova. Long standing collaboration is also ongoing with the University of Leuven and the University of Navarra.
Fig. 1: Morphologic and functional heterogeneity of biliary epithelium. The intrahepatic bile duct epithelium is organized as a three-dimensional network of interconnecting conduits of different sizes inside the liver irrorated by a periductular capillary plexus that originates from branches of the hepatic artery (HA). The biliary tree begins with the canals of Hering that constitutes a facultative progenitor cell compartment and connects hepatocytes with bile ducts. Cells lining the intrahepatic biliary tree have different functional and morphologic specializations: the cholangioles (size <15 µm) have some biologic properties such as plasticity, (ie, the ability to undergo limited phenotypic changes) and reactivity (ie, the ability to participate in the inflammatory reaction to liver damage); large size cholangiocytes (300-800 µm) modulates fluidity and alkalinity of the primary hepatocellular bile trough numerous different molecules located on their apical (luminal) and basolateral domain finally regulated by a complex of hormones, neuropeptides, and neurotransmitters.
Fig. 2: Dual-immunofluorescence staining of liver sections from ADPKD and Caroli's disease highlightes the major phenotypic differences between the two cystic cholangiopathies. In ADPKD double staining of the biliary cell marker HEA-125 (red fluorescence) with VEGF (green fluorescence, A) and Ang-1 (green fluorescence, B) confirms that these angiogenic factors strongly co-localize (yellow fluorescence) to bile duct epithelium. In Caroli's disease double staining of HEA-125 (red fluorescence) with VEGF (green fluorescence, D) and Ang-1 (green fluorescence, E) reveals co-localization (yellow fluorescence) to cholangiocytes for VEGF only. Original magnifications: A and C-D: x600, B x400.
Campus Address
Department of Internal Medicine
333 Cedar Street (LMP 1080)
New Haven, CT 06520
E-mail
mario.strazzabosco@yale.edu
Office Phone
(203) 737-6060
©
Yale School of Medicine
Last updated
1/15/08
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