Abstract
Certain human diseases affecting the biliary tree can be modeled in rats by ingestion of the hepatobiliary toxin alpha-naphthylisothiocyanate (ANIT). Phosphorus magnetic resonance spectroscopy (MRS) allows the noninvasive monitoring of cell dynamics through detection of phosphodiesters (PDE) and phosphomonoesters (PME). Hepatic (31)P MRS techniques were therefore used to study the toxic effects of low-dose chronic ANIT ingestion, with a view toward providing biomarkers sensitive to hepatobiliary dysfunction and cholestatic liver injury. Rats were fed an ANIT supplemented diet at three doses (ANIT_0.05%, ANIT_0.04%, and ANIT_0.025%) for 2 weeks. Data from in vivo MRS were compared with results from pair-fed controls (PFCs). Blood and tissue samples were collected at 2 weeks for clinical chemistry, histology, and (1)H magic angle spinning MRS. Increases in PDE, relative to total phosphorus (tPh), were detected in both the ANIT_0.05% and ANIT_0.04% groups (0.07 ± 0.01 and 0.08 ± 0.01, respectively) relative to PFC groups (0.03 ± 0.01 and 0.05 ± 0.01, respectively). An increase in PME/tPh was observed in the ANIT_0.05% group only (0.17 ± 0.02) relative to PFC_0.05% (0.12 ± 0.01). Ex vivo (1)H MRS findings supported this, wherein measured phosphocholines (PCs) were increased in ANIT_0.05% and ANIT_0.04% groups. Increases in relative total choline (tCho) distinguished the ANIT_0.05% group from the ANIT_0.04% group. Markers of hepatotoxicity such as raised total bilirubin and alkaline phosphatase were found at all ANIT doses. Histological findings included a dose-related increase in both severity of biliary hyperplasia and focal hepatocellular necrosis. Here, we found that ANIT-induced moderate hepatobiliary dysfunction was associated with a relative increase in phosphodiesters in vivo and PCs ex vivo. Raised PME/tPh in vivo and tCho ex vivo were also present at high doses corresponding to a higher incidence of marked biliary hyperplasia and moderate hepatocellular necrosis.
Highlights
ResultsFlow-based adhesion assays using human HSEC demonstrated that B cells were captured from flow and adhered to human HSEC but they had limited motility in comparison to T cells
Hepatobiliary injury, associated with intrahepatic cholestasis and biliary hyperplasia, is a commonly encountered adverse effect in man in response to certain drugs and toxins
Aim To investigate the use of in vivo hepatic phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) to provide potential biomarkers for hepatobiliary injury linked to biliary hyperplasia in the ANIT-fed rat model and to investigate longitudinal changes according to dose over a 2-week time period
Summary
TF and fibrin/fibrinogen were expressed in hepatic sinusoids, peri-fibrotic areas and fibrotic septa. Digital image analysis demonstrated significant upregulation of TF (p1⁄40.002) and fibrin/fibrinogen (p1⁄40.009) in fibrotic vs normal control liver tissue. In HCV human liver tissue, TF and fibrin/ fibrinogen were expressed in hepatic sinusoids and fibrotic areas. Digital image analysis demonstrated a significant correlation between TF expression and both fibrosis grade (r1⁄40.71; p1⁄40.015) and inflammatory score (r1⁄40.79; p1⁄40.004). Fibrin/fibrinogen expression was significantly correlated with inflammatory score (r1⁄40.82; p1⁄40.007), with a borderline correlation with grade of fibrosis (r1⁄40.66; p1⁄40.056). Conclusion The hepatic expression of TF and fibrin/fibrinogen is upregulated with fibrosis and inflammation. These findings suggest that activation of the coagulation cascade occurs in and may contribute to the generation of hepatic fibrosis.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
