6 mL CCl4/kg body weight; thrice weekly for 4 weeks; n = 3 mice per group), a three-dimensional high-resolution inversion recovery gradient echo delayed-enhancement MRI (DE-MRI; see Makowski et CT99021 purchase al.[4] for details on MR parameters and methodology) of liver tissue indicated clear differences between normal and diseased animals
(Fig. 1): while healthy livers displayed no focal contrast enhancement upon ESMA administration (Fig. 1D,E), very distinct perivascular signals were observed in large and medium-sized vessels in fibrotic livers (Fig. 1A,B). This observation was in line with periportal ECM deposition visualized using Elastica-Van-Gieson staining (Fig. 1C,F). Although these findings require further investigation (with
regard to fibrosis stage, ESMA dose, timing, specificity, and quantification), they demonstrate that elastin-based molecular MRI, like collagen-based molecular MRI,[3] may be suitable for noninvasive monitoring of ECM remodeling during liver fibrosis. As the collagen-to-elastin-ratio changes during the progression and regression of liver fibrosis,[2] the selective or combined use of different molecular MR probes might be a promising strategy for translating the differential regulation of ECM proteins during fibrosis pro- and regression into novel noninvasive imaging techniques for the clinic. Supported by the German Research Foundation (DFG SFB/TRR57; TA434/2-1; https://www.selleckchem.com/products/midostaurin-pkc412.html EH412/1-1; LA2937/1-1) and British Heart Foundation (RG/12/1/29262). ESMA was kindly provided by David Onthank (Lantheus Medical Imaging, North Billerica, MA). “
“The mechanism of idiosyncratic drug-induced liver injury (IDILI) remains poorly understood, to a large degree because of the lack of a valid animal model. Recently, we reported an animal model in which treatment of female C57BL/6 mice with amodiaquine (AQ) resulted in mild liver injury with a delayed onset and resolution despite continued treatment. Such adaptation is a common much outcome in the IDILI caused by drugs that can cause liver failure. We had hypothesized that most IDILI is immune mediated and adaptation represents immune tolerance. In this study
we found that AQ treatment of Cbl-b-/- and PD-1-/- mice, which have impaired immune tolerance, resulted in a slightly greater injury. Co-treatment of C57BL/6 with AQ and anti-CTLA4 also resulted in a greater increase in ALT than treatment with AQ alone; however, these mice also had an increase in Treg cells, and T helper cells expressing PD-1 and CTLA4. The increase in these cells implies the induction of immune tolerance, and the ALT activity in these mice returned to normal despite continued treatment. Co-treatment of PD-1-/- mice with anti-CTLA4 antibody and AQ resulted in the greatest increase in ALT (200 – 300 U/L), and necroinflammatory responses characterized by portal infiltration of lymphocytes with interface hepatitis.
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