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Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease.

Sharon D, Chen M, Zhang G, Girgis S, Sis B, Graham D, McDougall C, Wasilenko ST, Montano-Loza A, Mason AL - Liver Int. (2014)

Bottom Line: Response to treatment was studied by measuring MMTV RNA in the liver, liver enzyme levels in serum and liver histology using a modified Ishak score.Combination therapy with the reverse transcriptase inhibitors, tenofovir and emtricitabine, resulted in a significant reduction in serum liver enzyme levels, attenuation of cholangitis and decreased MMTV levels in the livers of NOD.c3c4 mice.Furthermore, treatment with the retroviral protease inhibitors, lopinavir and ritonavir, in addition to the reverse transcriptase inhibitors, resulted in further decrease in MMTV levels and attenuation of liver disease in this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.

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Serum alkaline phosphatase levels in NOD.c3c4 receiving no antiretroviral therapy. (A) Serial measurement of serum alkaline phosphatase in the NOD.c3c4 mice showing variance in individual levels as well as a reduction mean levels as mice aged, mainly from 8 to 12 weeks (P < 0.0001, 1 way anova). (B) Reduction in serum alkaline phosphatase levels from baseline levels between 8 and 12 weeks, showing diminished reduction in NOD.c3c4 vs. NOD.GFP (Data shown as means ± SEM, ***P < 0.001, t-test).
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fig01: Serum alkaline phosphatase levels in NOD.c3c4 receiving no antiretroviral therapy. (A) Serial measurement of serum alkaline phosphatase in the NOD.c3c4 mice showing variance in individual levels as well as a reduction mean levels as mice aged, mainly from 8 to 12 weeks (P < 0.0001, 1 way anova). (B) Reduction in serum alkaline phosphatase levels from baseline levels between 8 and 12 weeks, showing diminished reduction in NOD.c3c4 vs. NOD.GFP (Data shown as means ± SEM, ***P < 0.001, t-test).

Mentions: Prior studies have reported that NOD.c3c4 mice develop progressive cholangitis and biliary cysts with increasing age that leads to liver failure in 50% of females within a year. However, the occurrence of liver disease was previously assessed by the detection of extrahepatic biliary dilatation and the penetrance of disease was variable 2,3. Since we were interested in determining whether antiretroviral therapy may attenuate cholangitis development in this mouse model, we assessed the serum alkaline phosphatase levels during the 12 weeks of the study in the placebo arm without any intervention. We observed that the alkaline phosphatase levels fell without any intervention, mainly between weeks 8–12 (Fig.1A) and therefore investigated whether a similar reduction was observed in the parental derived strain, NOD.GFP mice (Fig.1B). A reduction in alkaline phosphatase levels was observed in both the NOD.c3c4 and the NOD strains suggesting that the decrease was related to puberty 23. Owing to the variability in levels prior to intervention, we chose to study the overall reduction in alkaline phosphatase from baseline.


Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease.

Sharon D, Chen M, Zhang G, Girgis S, Sis B, Graham D, McDougall C, Wasilenko ST, Montano-Loza A, Mason AL - Liver Int. (2014)

Serum alkaline phosphatase levels in NOD.c3c4 receiving no antiretroviral therapy. (A) Serial measurement of serum alkaline phosphatase in the NOD.c3c4 mice showing variance in individual levels as well as a reduction mean levels as mice aged, mainly from 8 to 12 weeks (P < 0.0001, 1 way anova). (B) Reduction in serum alkaline phosphatase levels from baseline levels between 8 and 12 weeks, showing diminished reduction in NOD.c3c4 vs. NOD.GFP (Data shown as means ± SEM, ***P < 0.001, t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403978&req=5

fig01: Serum alkaline phosphatase levels in NOD.c3c4 receiving no antiretroviral therapy. (A) Serial measurement of serum alkaline phosphatase in the NOD.c3c4 mice showing variance in individual levels as well as a reduction mean levels as mice aged, mainly from 8 to 12 weeks (P < 0.0001, 1 way anova). (B) Reduction in serum alkaline phosphatase levels from baseline levels between 8 and 12 weeks, showing diminished reduction in NOD.c3c4 vs. NOD.GFP (Data shown as means ± SEM, ***P < 0.001, t-test).
Mentions: Prior studies have reported that NOD.c3c4 mice develop progressive cholangitis and biliary cysts with increasing age that leads to liver failure in 50% of females within a year. However, the occurrence of liver disease was previously assessed by the detection of extrahepatic biliary dilatation and the penetrance of disease was variable 2,3. Since we were interested in determining whether antiretroviral therapy may attenuate cholangitis development in this mouse model, we assessed the serum alkaline phosphatase levels during the 12 weeks of the study in the placebo arm without any intervention. We observed that the alkaline phosphatase levels fell without any intervention, mainly between weeks 8–12 (Fig.1A) and therefore investigated whether a similar reduction was observed in the parental derived strain, NOD.GFP mice (Fig.1B). A reduction in alkaline phosphatase levels was observed in both the NOD.c3c4 and the NOD strains suggesting that the decrease was related to puberty 23. Owing to the variability in levels prior to intervention, we chose to study the overall reduction in alkaline phosphatase from baseline.

Bottom Line: Response to treatment was studied by measuring MMTV RNA in the liver, liver enzyme levels in serum and liver histology using a modified Ishak score.Combination therapy with the reverse transcriptase inhibitors, tenofovir and emtricitabine, resulted in a significant reduction in serum liver enzyme levels, attenuation of cholangitis and decreased MMTV levels in the livers of NOD.c3c4 mice.Furthermore, treatment with the retroviral protease inhibitors, lopinavir and ritonavir, in addition to the reverse transcriptase inhibitors, resulted in further decrease in MMTV levels and attenuation of liver disease in this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.

Show MeSH
Related in: MedlinePlus