Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • Based on these unique phenotypic

    2019-07-08

    Based on these unique phenotypic traits, a potential PBC model should include positive testing for AMA, histological evidence of interlobular bile duct injury, preferably with granuloma formation, and female predominance. The first attempts to develop a PBC animal model were performed by transferring peripheral blood mononuclear cells (PBMC) from PBC patients into severe combined immunodeficient (SCID) mice, but these first mouse models did not prove to be successful due to the lack of PBC-like morphology and the technical difficulties making them scarcely reproducible [81] (Fig. 2). Afterwards, several new murine models of PBC have been generated, and they can be clustered into spontaneous models employing genetically modified mice and inducible models, with the aid of xenobiotics harboring structural similarities to PDC-E2 (molecular mimicry) or self-biliary Prostaglandin J2 (Table 3).
    Conclusion
    Transparency document
    Acknowledgements
    Introduction Cystic Fibrosis (CF) is a life-threatening autosomal recessive disease with high incidence in the Caucasian population [1]. CFTR, the gene mutated in CF encodes a PKA/cAMP-activated chloride ion channel belonging to the family of the ATP binding cassette (ABC) transporter superfamily. CFTR is commonly expressed by secretory epithelia and CF is considered a multi-organ disease [[1], [2], [3]]. Liver disease is a severe complication in cystic fibrosis and represents the third most common cause of death for non-pulmonary causes [4]. Cystic Fibrosis Liver Disease (CFLD) is phenotypically characterized by distinct liver alterations that may vary from abnormal liver enzymes, cholestasis, sclerosing cholangitis type of lesions that progress to focal biliary cirrhosis and often in association with micro gallbladder and liver steatosis [5,6]. CFTR is specifically expressed on the apical membrane of biliary epithelial cells (i.e. cholangiocytes) where it maintains the chloride ion gradient that drives the secretion into the bile of bicarbonate by anion exchange-2 (AE2) and consequently the level of alkalization and hydration of the bile [7,8]. The pathogenetic mechanisms leading to the liver disease are still under investigation. A defective biliary secretion caused by the CFTR dysfunction is the primary event but secondary insults are at a play to drive the progression and severity of the disease [9,10]. Important advances in the field have been possible thanks to the availability of animal models. CF researchers have made available a wide range of animal models that include different species from small rodents to larger mammals. Each of these models reproduce different aspects of the disease, however, together they can be informative on the impact of CFTR function in pathophysiology of the disease and how it correlates with different phenotypes [11,12]. The development of novel genome targeting technique will bring new advances to already existing models and possibly help the search for curative options [13].
    Murine models and hepatobiliary disease development Mutations of CFTR result in different grades of dysfunction of the channel at the membrane of secretory epithelia [14]. To date, approximately 2000 mutations have been identified, but unfortunately the functional importance is known for only about 200 of them. Based on their functional alterations, most common mutations have been grouped into six different classes that include mutations with a complete absence of CFTR protein (Class I), with an altered traffic of a misfolded protein that does not reach the apical membrane (Class II), where CFTR protein is produced and inserted at the membrane but lacks channel function (Class III), and with different degree of reduction of the channel function (Classes IV–VI) [15]. The most common mutation is the deletion of a phenylalanine at the position 508 (F508del) that accounts for about 75% of mutated alleles in the European and North American population. This class II mutation produces a misfolded protein (not trafficking to the plasma membrane), with defective gating and decreased CFTR half-life when rescued. Class I-III mutations are causing the most severe defects [14,15].