Immunohistochemical Characterization of Macrophages and Myofibroblasts in α-Naphthylisothiocyanate (ANIT)–Induced Bile Duct Injury and Subsequent Fibrogenesis in Rats

Golbar, Hossain M.; Izawa, Takeshi; Yano, Ryo; Ichikawa, Chisa; Sawamoto, Osamu; Kuwamura, Mitsuru; LaMarre, Jonathan; Yamate, Jyoji

doi:10.1177/0192623311413790

Cited by 25 publications

(27 citation statements)

References 42 publications

(53 reference statements)

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“…1 and Supplementary Fig. 11) and liver enzymes [28] (Supplementary Table 1) were different between Notch-2 -cKO, RBP-Jκ -cKO mice and WT littermates. In WT mice, both damage protocols stimulated a DR, with increased HPCs, dysmorphic bile ducts and mature bile ducts [2].…”

Section: Resultsmentioning

confidence: 99%

Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice

Fiorotto

Raizner

Morell

et al. 2013

Journal of Hepatology

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Background & Aims Repair from biliary damages requires the biliary specification of hepatic progenitor cells and the remodeling of ductular reactive structures into branching biliary tubules. We hypothesized that the morphogenetic role of Notch signaling is maintained during the repair process and have addressed this hypothesis using pharmacologic and genetic models of defective Notch signaling. Methods Treatment with DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) or ANIT (alpha-naphthyl-isothiocyanate) was used to induce biliary damage in wild type mice and in mice with a liver specific defect in the Notch-2 receptor (Notch-2-cKO) or in RPB-Jk. Hepatic progenitor cells, ductular reaction, and mature ductules were quantified using K19 and SOX-9. Results In DDC treated wild type mice, pharmacologic Notch inhibition with dibenzazepine decreased the number of both ductular reaction and hepatic progenitor cells. Notch-2-cKO mice treated with DDC or ANIT accumulated hepatic progenitor cells that failed to progress into mature ducts. In RBP-Jk-cKO mice, mature ducts and hepatic progenitor cells were both significantly reduced with respect to similarly treated wild type mice. The mouse progenitor cell line BMOL cultured on matrigel, formed a tubular network allowing the study of tubule formation in vitro; γ-secretase inhibitor treatment and siRNAs silencing of Notch-1, Notch-2 or Jagged-1 significantly reduced both the length and number of tubular branches. Conclusions These data demonstrate that Notch signaling plays an essential role in biliary repair. Lack of Notch-2 prevents biliary tubule formation, both in vivo and in vitro. Lack of RBP-Jk inhibits the generation of biliary-committed precursors and tubule formation.

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Section: Resultsmentioning

confidence: 99%

Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice

Fiorotto

Raizner

Morell

et al. 2013

Journal of Hepatology

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“…Rats taken in alpha naphthylisothiocyanate (ANIT) have been one of the most common experimental models of intrahepatic cholestasis and used extensively, which was permitted to describe not only cholestatic alterations but also compensatory mechanisms [30]. The liver in ANIT-treated rats showed cholangiolitic hepatitis characterized by intrahepatic cholestasis, necrosis of hepatocytes and biliary epithelial cells and bile obstruction [31]. …”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory and anti-oxidative effects of corilagin in a rat model of acute cholestasis

Jin

Cheng

Tao³

et al. 2013

BMC Gastroenterol

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BackgroundNowadays, treatments for cholestasis remain largely nonspecific and often ineffective. Recent studies showed that inflammatory injuries and oxidative stress occur in the liver with cholestasis. In this study, we would use corilagin to treat the animal model of acute cholestasis in order to define the activity to interfere with inflammation-related and oxidative stress pathway in cholestatic pathogenesis.MethodsRats were administrated with alpha-naphthylisothiocyanate to establish model of cholestasis and divided into corilagin, ursodeoxycholic acid, dexamethasone, model and normal groups with treatment of related agent. At 24h, 48h and 72h time points after administration, living condition, serum markers of liver damage, pathological changes of hepatic tissue, nuclear factor (NF)-kappaB, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO) were examined and observed.ResultsCompared to model group, corilagin had remarkable effect on living condition, pathological manifestation of liver tissue, total bilirubin, direct bilirubin, (P<0.01), but no effect on alanine aminotransferase (ALT) and aspartate aminotransferase (AST). With corilagin intervention, levels of MPO, MDA and translocation of NF-κB were notably decreased, and levels of SOD and NO were markedly increased (P<0.05 or P<0.01).ConclusionsIt is shown that corilagin is a potential component to relieve cholestasis through inflammation-related and oxidation-related pathway.

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“…Tissues from the left lateral lobe of the livers were fixed in 10% neutral-buffered formalin, Zamboni's fixative (0.21% picric acid and 2% paraformaldehyde in 130 mM phosphate buffer, pH 7.4), and periodate-lysine-paraformaldehyde (PLP) solutions (Golbar et al 2011). These tissues were dehydrated, embedded in paraffin, sectioned (4 μm), and stained with H&E for histopathology and von Kossa's stain for calcium staining.…”

Section: Histopathology and Immunohistochemistrymentioning

confidence: 99%

Depletion of Hepatic Macrophages Aggravates Liver Lesions Induced in Rats by Thioacetamide (TAA)

et al. 2016

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Hepatic macrophages play crucial roles in hepatotoxicity. We investigated immunophenotypes of macrophages in liver injury induced in rats by thioacetamide (TAA; 300 mg/kg, intraperitoneal) after hepatic macrophage depletion; hepatic macrophages were depleted by liposomal clodronate (CLD; 10 ml/kg, i.v.) one day before TAA injection. Samples were obtained on post-TAA injection days 0, 1, 2, 3, 5, and 7. TAA injection induced coagulation necrosis of hepatocytes on days 1 through 3 and subsequent reparative fibrosis on days 5 and 7 in the centrilobular area, accompanied by increased numbers of M1 macrophages (expressing cluster of differentiation [CD]68 and major histocompatibility complex class II) and M2 macrophages (expressing CD163 and CD204) mainly on days 1 through 3. TAA þ CLD treatment markedly decreased the numbers of M1 and M2 macrophages mainly on days 1 through 3; CD163 þ Kupffer cells were most sensitive to CLD depletion. In TAA þ CLD-treated rats, interestingly, coagulation necrosis of hepatocytes was prolonged with more increased levels of hepatic enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase) to TAA-treated rats; reparative fibrosis was incomplete and replaced by dystrophic calcification in the injured area, indicating the aggravated damage. Furthermore, in TAA þ CLD-treated rats, inflammatory factors (monocyte chemoattractant protein [MCP]-1, interferon-g, tumor necrosis factor-a, and interleukin-10) and fibrosis-related factors (transforming growth factor-b1, matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1) were decreased at messenger RNA levels, indicating abnormal macrophage functions. It was clearly demonstrated that hepatic macrophages have important roles in tissue damage and remodeling in hepatotoxicity.

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Immunohistochemical Characterization of Macrophages and Myofibroblasts in α-Naphthylisothiocyanate (ANIT)–Induced Bile Duct Injury and Subsequent Fibrogenesis in Rats

Cited by 25 publications

References 42 publications

Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice

Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice

Anti-inflammatory and anti-oxidative effects of corilagin in a rat model of acute cholestasis

Depletion of Hepatic Macrophages Aggravates Liver Lesions Induced in Rats by Thioacetamide (TAA)

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