Bile canalicular abnormalities in the early phase of a mouse model of sclerosing cholangitis

Miyao, Masashi; Ozeki, Munetaka; Abiru, Hitoshi; Manabe, Sho; Kotani, Hirokazu; Tsuruyama, Tatsuaki; Tamaki, Keiji

doi:10.1016/j.dld.2012.09.007

Cited by 13 publications

(18 citation statements)

References 40 publications

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“…Recently, morphological studies confirmed hepatocellular necrosis and phagocytosis of these necrotic cells by Kupffer cells and showed compensatory hepatocyte proliferation in response to DDC-induced injury. This study also revealed that bile canalicular abnormalities occur prior to ductular reactions and periductal fibrosis in this novel xenobiotic induced model of primary sclerosing cholangitis [118]. This was the first study showing these characteristics associated with progression of PSC.…”

Section: Mouse Models That Mimic Specific Human Diseasesmentioning

confidence: 75%

Mouse Models of Liver Fibrosis Mimic Human Liver Fibrosis of Different Etiologies

et al. 2014

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The liver has the amazing capacity to repair itself after injury; however, the same processes that are involved in liver regeneration after acute injury can cause serious consequences during chronic liver injury. In an effort to repair damage, activated hepatic stellate cells trigger a cascade of events that lead to deposition and accumulation of extracellular matrix components causing the progressive replacement of the liver parenchyma by scar tissue, thus resulting in fibrosis. Although fibrosis occurs as a result of many chronic liver diseases, the molecular mechanisms involved depend on the underlying etiology. Since studying liver fibrosis in human subjects is complicated by many factors, mouse models of liver fibrosis that mimic the human conditions fill this void. This review summarizes the general mouse models of liver fibrosis and mouse models that mimic specific human disease conditions that result in liver fibrosis. Additionally, recent progress that has been made in understanding the molecular mechanisms involved in the fibrogenic processes of each of the human disease conditions is highlighted.

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Section: Mouse Models That Mimic Specific Human Diseasesmentioning

confidence: 75%

Mouse Models of Liver Fibrosis Mimic Human Liver Fibrosis of Different Etiologies

et al. 2014

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“…(33,34) As described previously, CEACAM1 is highly expressed in bile canaliculi in the liver of rodents and humans and recognized as one of the most sensitive parameters for early diagnosis of cholangiopathy in various pathological conditions. (34) After antigen retrieval, quenching, and blocking, the paraffin sections were incubated with the primary mouse anti-rat CEACAM1 antibody (clone11-1H; Merck, Darmstadt, Germany), followed by incubation with the second antibody. The stains were visualized with 3,3′-diaminobenzidine tetrahydrochloride solution, counterstained with hematoxylin-eosin, and observed with a BZ-9000 microscope (Keyence, Osaka, Japan).…”

Section: Immunohistochemistry For Ceacam1mentioning

confidence: 90%

“…Immunohistochemical staining for carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) was performed to assess the integrity of bile canaliculi . As described previously, CEACAM1 is highly expressed in bile canaliculi in the liver of rodents and humans and recognized as one of the most sensitive parameters for early diagnosis of cholangiopathy in various pathological conditions . After antigen retrieval, quenching, and blocking, the paraffin sections were incubated with the primary mouse anti‐rat CEACAM1 antibody (clone11‐1H; Merck, Darmstadt, Germany), followed by incubation with the second antibody.…”

Section: Methodsmentioning

confidence: 99%

Hydrogen Flush After Cold Storage as a New End‐Ischemic Ex Vivo Treatment for Liver Grafts Against Ischemia/Reperfusion Injury

Tamaki¹,

Hata²,

Okamura³

et al. 2018

Liver Transpl

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Cold storage (CS) remains the gold standard for organ preservation worldwide, although it is inevitably associated with ischemia/reperfusion injury (IRI). Molecular hydrogen (H ) is well known to have antioxidative properties. However, its unfavorable features, ie, inflammability, low solubility, and high tissue/substance permeability, have hampered its clinical application. To overcome such obstacles, we developed a novel reconditioning method for donor organs named hydrogen flush after cold storage (HyFACS), which is just an end-ischemic H flush directly to donor organs ex vivo, and, herein, we report its therapeutic impact against hepatic IRI. Whole liver grafts were retrieved from Wistar rats. After 24-hour CS in UW solution, livers were cold-flushed with H solution (1.0 ppm) via the portal vein (PV), the hepatic artery (HA), or both (PV + HA). Functional integrity and morphological damages were then evaluated by 2-hour oxygenated reperfusion at 37°C. HyFACS significantly lowered portal venous pressure, transaminase, and high mobility group box protein 1 release compared with vehicle-treated controls (P < 0.01). Hyaluronic acid clearance was significantly higher in the HyFACS-PV and -PV + HA groups when compared with the others (P < 0.01), demonstrating the efficacy of the PV route to maintain the sinusoidal endothelia. In contrast, bile production and lactate dehydrogenase leakage therein were both significantly improved in HyFACS-HA and -PV + HA (P < 0.01), representing the superiority of the arterial route to attenuate biliary damage. Electron microscopy consistently revealed that sinusoidal ultrastructures were well maintained by portal HyFACS, while microvilli in bile canaliculi were well preserved by arterial flush. As an underlying mechanism, HyFACS significantly lowered oxidative damages, thus improving the glutathione/glutathione disulfide ratio in liver tissue. In conclusion, HyFACS significantly protected liver grafts from IRI by ameliorating oxidative damage upon reperfusion in the characteristic manner with its route of administration. Given its safety, simplicity, and cost-effectiveness, end-ischemic HyFACS may be a novel pretransplant conditioning for cold-stored donor organs.

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“…5 It has been demonstrated that sinusoidal capillarization precedes liver fibrosis in various liver diseases, including NAFLD, 6,7 and our previous study using a cholangiopathy model also demonstrated that capillarization appeared before liver fibrosis. 8 Furthermore, Xie et al recently reported that capillarization has a pivotal role in hepatic stellate cell (HSC) activation and fibrogenesis during the late stage in a rat liver fibrosis model, 9 and LSECs have been speculated to have an anti-inflammatory role in cooperation with Kupffer cells, and to have a pivotal role for fibrogenesis by promoting HSC activation. [10][11][12] However, the relationship between sinusoidal capillarization and NAFLD progression and the interactions of LSECs with these cells in the different stages of NAFLD remain largely unknown.…”

mentioning

confidence: 99%

Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression

Miyao

Kotani

Ishida

et al. 2015

Laboratory Investigation

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181

145

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Liver sinusoidal endothelial cells (LSECs) are involved in the transport of nutrients, lipids, and lipoproteins, and LSEC injury occurs in various liver diseases including nonalcoholic fatty liver disease (NAFLD). However, the association between LSEC injury and NAFLD progression remains elusive. Accordingly, in this study, we aimed to elucidate the precise role of LSEC in the pathophysiology of NAFLD using two different mouse models, namely the choline-deficient, L-amino acid-defined and high-fat diet models. Administration of these diets resulted in liver metabolic dysregulation mimicking human NAFLD, such as steatosis, ballooning, lobular inflammation, and fibrosis, as well as central obesity, insulin resistance, and hyperlipidemia. LSEC injury appeared during the simple steatosis phase, and preceded the appearance of activated Kupffer cells and hepatic stellate cells (HSCs). These results indicate that LSEC injury may have a 'gatekeeper' role in the progression from simple steatosis to the early nonalcoholic steatohepatitis (NASH) stage, and LSEC injury may be necessary for the activation of Kupffer cells and HSCs, which in turn results in the development and perpetuation of chronic liver injuries. Taken together, our data provide new insights into the role of LSEC injury in NAFLD/NASH pathogenesis.

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Bile canalicular abnormalities in the early phase of a mouse model of sclerosing cholangitis

Abstract: This study provides novel evidence of the occurrence of bile canalicular abnormalities during the early phase of sclerosing cholangitis.

Cited by 13 publications

References 40 publications

Mouse Models of Liver Fibrosis Mimic Human Liver Fibrosis of Different Etiologies

Mouse Models of Liver Fibrosis Mimic Human Liver Fibrosis of Different Etiologies

Hydrogen Flush After Cold Storage as a New End‐Ischemic Ex Vivo Treatment for Liver Grafts Against Ischemia/Reperfusion Injury

Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression

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