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![Taurine reduced the degeneration of extrahepatic bile duct. 3D reconstructed confocal images of liver during developmental biliary atresia in sea lamprey. Cysteine sulfinic acid decarboxylase (CSAD) siRNA treatment facilitated degeneration of the extrahepatic bile duct (white arrows). Blue immunofluorescence staining: caspase 3 (apoptosis marker). Green immunofluorescence staining: BCL2 (apoptosis protection marker). Red immunofluorescence staining: CSAD (the rate limiting enzyme for taurine biosynthesis). Whole livers were processed with a modified CLARITY method [122]. Scale bar: 500 μm.](publication/277305236/figure/fig27/AS:1088567153569794@1636546042045/Taurine-reduced-the-degeneration-of-extrahepatic-bile-duct-3D-reconstructed-confocal.jpg)
Taurine reduced the degeneration of extrahepatic bile duct. 3D reconstructed confocal images of liver during developmental biliary atresia in sea lamprey. Cysteine sulfinic acid decarboxylase (CSAD) siRNA treatment facilitated degeneration of the extrahepatic bile duct (white arrows). Blue immunofluorescence staining: caspase 3 (apoptosis marker). Green immunofluorescence staining: BCL2 (apoptosis protection marker). Red immunofluorescence staining: CSAD (the rate limiting enzyme for taurine biosynthesis). Whole livers were processed with a modified CLARITY method [122]. Scale bar: 500 μm.
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Biliary atresia (BA) is a progressive, inflammatory, and fibrosclerosing cholangiopathy in infants that results in obstruction of both extrahepatic and intrahepatic bile ducts. It is the most common cause for pediatric liver transplantation. In contrast, the sea lamprey undergoes developmental BA with transient cholestasis and fibrosis during metam...
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Biliary atresia (BA) is a rare neonatal disease with unknown causes. Approximately 10% of BA cases develop in utero with other congenital defects that span a large spectrum of disease variations, including degeneration of the gall bladder and bile duct as well as malformation of the liver, intestines, and kidneys. Similar developmental alterations...
Citations
Cholestasis is a main clinical feature of biliary atresia (BA), which leads to liver fibrosis (LF). The focus of BA treatment is preventing and slowing the progress of LF. This study reports the improvement effect of anlotinib on common bile duct ligature (BDL)‐induced LF in young rats. The BDL young rats were treated with anlotinib and the serum levels of aspartate aminotransferase, alanine aminotransferase, albumin, and total bilirubin were determined. Histological staining was performed and pathological changes in liver tissue were observed. The expression levels of α‐SMA, collagen I, CD31, TGF‐β1, phospho‐VEGFR2, phospho‐4E/BP1, and phospho‐S6K1 were determined. The results showed that anlotinib significantly improved the liver function and histopathological injury of BDL rats, inhibited the deposition of collagen and hepatocyte apoptosis, and downregulated the protein expression of α‐SMA and collagen I. Furthermore, anlotinib treatment significantly inhibited microvascular formation in the liver and downregulated the expression level of phospho‐VEGFR2, thereby suggesting that the antifibrosis effect of anlotinib may be achieved by antiangiogenesis. In addition, anlotinib downregulated the expression of phospho‐S6K1 and upregulated the expression of phospho‐4E/BP1, two downstream proteins of the mammalian target of rapamycin (mTOR) pathway. MHY1485, an agonist of mTOR, significantly reversed the inhibitory effect of anlotinib on angiogenesis and LF but did not influence the effect of anlotinib on the downregulation of phospho‐VEGFR2 expression. Together, the above‐mentioned results suggest that the effect of anlotinib on BDL‐induced LF involves at least antiangiogenesis regulated by the VEGFR2/mTOR signaling pathway.
Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case per 10,000–20,000 live births, but the percentage may be higher, considering the late diagnoses. The etiology is heterogeneous. BA, which is considered in half of the causes leading to orthotopic liver transplantation, occurs in primates and non-primates. To consolidate any model, (1) more transport and cell membrane studies are needed to identify the exact mechanism of noxa-related hepatotoxicity; (2) an online platform may be key to share data from pilot projects and new techniques; and (3) the introduction of differentially expressed genes may be useful in investigating the liver metabolism to target the most intricate bilio-toxic effects of pharmaceutical drugs and toxins. As a challenge, such methodologies are still limited to very few centers, making the identification of highly functional animal models like finding a “needle in a haystack”. This review compiles models from the haystack and hopes that a combinatorial search will eventually be the root for a successful pathway.
Biliary atresia (BA) is a rare but severe fibroinflammatory disease of the extrahepatic and the intrahepatic bile ducts. Without prompt interventions, BA has fatal outcomes and is the most common indicator for pediatric liver transplantation (LTx). While the mainstay of treatment involves surgically correcting the extrahepatic biliary obstruction via Kasai hepato-portoenterostomy (KHPE), activation of a multitude of biological pathways and yet-to-be-determined etiology in BA continue to foster liver inflammation, cirrhosis and need for LTx. However, important caveats still exist in our understandings of the biliary pathophysiology, the rapidity of liver fibrosis and progression to liver failure, largely due to limited knowledge of the triggers of biliary injury and the inability to accurately model human BA. Although inconclusive, a large body of existing literature points to a potential viral infection in the early peri- or postnatal period as triggers of epithelial injury that perpetuates the downstream biliary disease. Further confounding this issue, are the lack of in-vivo and in-vitro models to efficiently recapitulate the cardinal features of BA, primarily liver fibrosis. To overcome these barriers in BA research, new directions in recent years have enabled (I) identification of additional triggers of biliary injury linked mostly to environmental toxins, (II) development of models to investigate liver fibrogenesis, and (III) translational research using patient-derived organoids. Here, we discuss recent advances that undoubtedly will stimulate future efforts investigating these new and exciting avenues towards mechanistic and drug discovery efforts and disease-preventive measures. The implications of these emerging scientific investigations and disease modeling in severe fibrosing cholangiopathies like BA are enormous and contribute substantially in our understandings of this rare but deadly disease. These findings are also expected to facilitate expeditious identification of translationally targetable pathways and bring us one step closer in treating an infant with BA, a population highly vulnerable to life-long liver related complications.
p>Biliary atresia leads to cirrhosis in the vast majority of patients and constitutes the first cause of paediatric liver transplantation. Animal models allow us to understand the molecular basis and natural history of diseases. The aim of this study is to describe a surgically created animal model of biliary atresia with emphasis in long-term liver function. Forty-two 3-week-old Sprague-Dawley rats were randomly divided into two groups: bile duct ligature (BDL) and control. The animals were sacrificed on the 2<sup>nd</sup>, 4<sup>th</sup>, and 6<sup>th</sup> postoperative weeks. Blood samples were collected for liver function analysis. The spleen to body weight ratio was determined. Histopathological examination of liver tissue was performed by hematoxylin-eosin and Sirius red staining. Collagen quantification was determined by using colorimetric digital image analysis and was expressed as a percentage of total liver tissue area. Quantitative real-time polymerase chain reaction was performed to analyse gene expression levels of transforming growth factor-β1 ( Tgfb1 ) and apeline ( Apln ) genes. Statistical analysis was performed where P<0.05 was considered significant. Animals from BDL group developed increasing cholestasis with clinical and laboratory features. Splenomegaly was detected at 4<sup>th</sup> and 6<sup>th</sup> week (P<0.05). Histological evaluation of the liver showed ductular reaction, portal fibrosis and bile plugs. Collagen area to total liver tissue area had a median of 2.5% in the control group and 6.5 %, 14.3 % and 37.7 % in BDL rats at 2<sup>nd</sup>, 4<sup>th</sup> and 6<sup>th</sup> weeks respectively (P<0.001). Tgfb1 mRNA expression level was significantly higher at 6<sup>th</sup> week (P<0.001) in BDL group when compared to control. Apln mRNA expression level was significantly higher at 4<sup>th</sup> and 6<sup>th</sup> week (P<0.001) and showed a positive linear correlation (r = 0.975, P<0.05) in BDL group when compared to control. Bile duct ligature in young rats is an animal model that recreates clinical, laboratory, histological and molecular findings of biliary atresia. Bile duct ligature constitutes a good animal model to investigate therapeutic approaches for modifying the progression of liver fibrosis in biliary atresia.</p
Biliary atresia is a rare disease of infancy with an estimated incidence in Europe of 1 in 15,000–19,000. The disease onset is confined to the neonatal period, and there is no equivalent liver disease outside of this period. It affects all races and ethnic groups, although black mothers are 2.5 times more likely to have a baby with biliary atresia than other ethnic groups. The pathogenesis of biliary atresia is unknown; and research to further understand the underlying mechanisms of its development is disadvantaged by the rarity of disease and lack of correlation between human and animal models. A remarkable medical achievement has been the Kasai portoenterostomy surgical procedure, which along with liver transplantation (when necessary) has increased survival into adulthood with a good quality of life.
The pathway from clinical suspicion to establishing the diagnosis of biliary atresia in a child with jaundice is a daunting task. However, investigations available help to point towards the correct diagnosis in reasonable time frame. Imaging by Sonography has identified several parameters which can be of utility in the diagnostic work up. Comparison of Sonography with imaging by Nuclear medicine can bring out the significant differences and also help in appropriate imaging. The battery of Biochemical tests, available currently, enable better understanding of the line-up of investigations in a given child with neonatal cholestasis. Management protocols enable standardized care with optimal outcome. The place of surgical management in biliary atresia is undisputed, although Kasai procedure and primary liver transplantation have been pitted against each other. This article functions as a platform to bring forth the various dimensions of biliary atresia.
Background:
Biliary atresia (BA) is a human infant disease with inflammatory fibrous obstructions in the bile ducts and is the most common cause for pediatric liver transplantation. In contrast, the sea lamprey undergoes developmental BA with transient cholestasis and fibrosis during metamorphosis, but emerges as a fecund adult. Therefore, sea lamprey liver metamorphosis may serve as an etiological model for human BA and provide pivotal information for hepatobiliary transformation and possible therapeutics.
Results:
We hypothesized that liver metamorphosis in sea lamprey is due to transcriptional reprogramming that dictates cellular remodeling during metamorphosis. We determined global gene expressions in liver at several metamorphic landmark stages by integrating mRNA-Seq and gene ontology analyses, and validated the results with real-time quantitative PCR, histological and immunohistochemical staining. These analyses revealed that gene expressions of protein folding chaperones, membrane transporters and extracellular matrices were altered and shifted during liver metamorphosis. HSP90, important in protein folding and invertebrate metamorphosis, was identified as a candidate key factor during liver metamorphosis in sea lamprey. Blocking HSP90 with geldanamycin facilitated liver metamorphosis and decreased the gene expressions of the rate limiting enzyme for cholesterol biosynthesis, HMGCoA reductase (hmgcr), and bile acid biosynthesis, cyp7a1. Injection of hsp90 siRNA for 4 days altered gene expressions of met, hmgcr, cyp27a1, and slc10a1. Bile acid concentrations were increased while bile duct and gall bladder degeneration was facilitated and synchronized after hsp90 siRNA injection.
Conclusions:
HSP90 appears to play crucial roles in hepatobiliary transformation during sea lamprey metamorphosis. Sea lamprey is a useful animal model to study postembryonic development and mechanisms for hsp90-induced hepatobiliary transformation.
