Lazzari, Roberta (2008) Ruolo del sistema endocannabinoide nella cirrosi biliare primitiva. [Tesi di dottorato]
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Endocannabinoid system (EC) has emerged as a crucial mediator in a variety of pathophysiological conditions. A cannabinoid agonist (WIN5521-2) has been shown to increase the pruritus threshold in cholestatic rats. Moreover, in the course of chronic cholangiopaties hepatic progenitor cells are activated constituting a neuroendocrine compartment regulated by different agents including neuropeptides. Aims: 1. To evaluate whether the EC system is activated in PBC; 2. To evaluate if genetic variations in human cannabinoid-specific receptor genes (CB1 and CB2) might cause a different phenotypic expression of the disease in terms of association with pruritus. Methods: 1) Morphological study: CB1 and CB2 receptors were characterized in biopsy specimens of 2 normal human liver and 9 PBC (IV stage) by immunohistochemistry. CB1 and CB2 mRNA expression was also assayed through RT-PCR in liver samples. 2) Genetic study: the following groups of subjects have been enrolled: 68 consecutive PBC Italian pts, 84 PBC pts residents in USA; 70 controls, matched for sex, age, and geographical area with the Italian PBC pts. Genomic DNA was extracted from peripheral venous blood leucocytes with standard method. PCR was used to amplify the coding regions of the CB1 and CB2 genes with specific primers. Results: in PBC, CB1 was markedly expressed in hepatocytes, biliary epithelial cells and in Kupffer cells; conversely, in control livers was virtually absent. CB2 was markedly expressed in hepatocytes and in biliary epithelial cells, in CBP.
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