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904A AASLD ABSTRACTS HEPATOLOGY, October, 2015 among the three groups(p=NS).Th17 cells were obviously reduced in AFMSC- IL-17RLM group as compared with blank groups(p6.5) relative to NAFL or NASH subjects without diabetes (ANOVA p=0.056), and correlated with HbA1c (r 2 =0.57). FSR of circulating plasma lumican, a proteoglycan involved in collagen fibril assembly, correlated with liver collagen FSR (r 2 =0.57) and with liver stiffness (r 2 =0.73). Conclusion: Hepatic collagen remodeling and synthesis rates are higher in NASH than NAFL, increase with fibrosis severity and track with diabetes, a risk factor for fibrosis progression. Plasma lumican FSR correlates closely with liver collagen FSR and liver stiffness. Non-invasive kinetic measurements may be helpful as early read outs of treatment response in anti-fibrotic trials. The elevated hepatic fibrosis rates in advanced disease suggest that hepatic scar is dynamic and potentially reversible.
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 905A Disclosures: Claire Emson - Employment: KineMed Martin Decaris - Employment: KineMed Inc. Scott M. Turner - Employment: KineMed, Inc. Carine Beysen - Employment: KineMed, Inc; Stock Shareholder: KineMed, Inc Kelvin Li - Employment: KineMed, Inc; Stock Shareholder: KineMed, Inc Rohit Loomba - Advisory Committees or Review Panels: Galmed Inc, Tobira Inc, Arrowhead Research Inc; Consulting: Gilead Inc, Corgenix Inc, Janssen and Janssen Inc, Zafgen Inc, Celgene Inc, Alnylam Inc, Inanta Inc, Deutrx Inc; Grant/ Research Support: Daiichi Sankyo Inc, AGA, Merck Inc, Promedior Inc, Kinemed Inc, Immuron Inc, Adheron Inc The following authors have nothing to disclose: Carolyn Hernandez, Jeffrey Y. Cui, Leander Lazaro, David A. Brenner, Marc Hellerstein 1426 In vivo cell specific gene silencing in the liver using novel siRNA-loaded nanohydrogel particles Leonard Kaps; Institute of Translational Immunology and Research Center for Immunotherapy (FZI), Mainz, Germany Background: Efficient in vivo transport of active siRNA to specific liver cells remains challenging. Compared to lipoplex or polyplex formulations, cationic nanohydrogel particles (NHP) can serve as superior oligonucleotide carriers [Siegwart DJ et al, PNAS 2011]. We have designed NHP [Nuhn L et al, ACS Nano 2012] that serve as stable carriers for in vivo siRNA delivery [Nuhn L et al, Biomacromolecules 2014]. Results: NHP composed of block copolymers loaded with negative control siRNA up to 600 nM siRNA and of a size of 30 to 40 nm did not show cytotoxicity for murine 3T3 fibroblasts, Raw or MHS macrophages, HepG2 human liver cells or AML-12 murine benign hepatocytes. In full media FITC-labelled NHP were taken up efficiently reaching up to 90% after 1 h incubation as determined by FACS analysis. NHP loaded with procollagen a1(I) or CD68 targeted siRNA yielded a robust knockdown in 3T3 and Raw cells, respectively, after 48 h of incubation as determined by qPCR. In vivo <strong>studies</strong> using near infrared labelled NHP loaded with Cy5 labelled procollagen a1(I) siRNA were performed in lCCl4 treated mice. After i.v. injection NHP accumulated in the liver (80%), as determined by in vivo and ex vivo near infrared imaging. IHC and ex vivo FACS analysis revealed a preferential colocalization with myofibroblasts (α-SMA+) and macrophages (CD45+ F4/80+ CD11b+). NHP loaded with procollagen a1(I) siRNA generated an up to 80% in vivo knockdown in CCl4-induced liver fibrosis. Efficient knockdown was further confirmed by decreased liver collagen (Sirius red staining and hydroxyproline content). Conclusions: siRNA loaded NHP accumulate in the liver and especially in (myo-) fibroblasts and macrophages/Kupffer cells. Due to their intrinsic specificity for nonparenchymal cells, an apparent lack of toxicity and a high loading capacity, they are attractive carriers for siRNA-based antifibrotic or immune modulatory therapies. Disclosures: The following authors have nothing to disclose: Leonard Kaps 1427 Host microbiota dictates the profibrotic impact of PAMPs in the liver Suriguga Suriguga 1 , Floris Fransen 2 , Dorenda Oosterhuis 1 , Geny M. Groothuis 3 , Paul D. Vos 2 , Henricus A. Mutsaers 1 , Peter Olinga 1 ; 1 Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, Netherlands; 2 Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands; 3 Division of Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, Groningen, Netherlands Background Pathogen-associated molecular patterns (PAMPs), e.g. lipopolysaccharide (LPS) and flagellin, might promote liver fibrosis via the gut-liver axis. However, how these bacterial components initiate fibrogenesis needs further clarification. In germ-free (GF) mice, the liver has no history of interaction with PAMPs, while in colonized (specific pathogen free, SPF) mice the liver is exposed to PAMPs. Therefore, this study was designed to investigate the possible fibrogenic effect of PAMPs in SPF and GF mice, using precision-cut liver slices (PCLS) as fibrosis model. Methods PCLS from SPF and GF mice were incubated with or without 10 mg/ml LPS or 50 ng/ml flagellin for 48h. Viability of PCLS was assessed by measuring their ATP content. Gene expression of key fibrosis markers Procollagen1α1 (Col1α1), α-Smooth Muscle Actin (α-SMA), Heat Shock Protein 47 (Hsp47), and Plasminogen Activator Inhibitor-1 (PAI-1) were determined by real-time qPCR. Results Both SPF and GF mice liver slices were viable up to 48h. Solely in SPF PCLS, we observed spontaneous onset of fibrosis during culture up to 48h. Yet, treatment with LPS or flagellin did not augment the fibrotic response. In contrast, in GF PCLS, Hsp47 expression was significantly up-regulated in the presence of LPS: 1.4-fold, while Col1α1 and α-SMA tended to increase compared to control slices incubated for 48h. PAI-1, a marker for transforming growth factor-β (TGF-β) pathway activation, was significantly elevated up to 81.8-fold in SPF and 37.2-fold in GF PCLS after culture (48h) compared to directly after slicing. Exposure to LPS further increased PAI-1 gene expression in GF PCLS (2.9-fold), but not in SPF mice. Moreover, in GF liver slices treatment with flagellin significantly increased expression of Col1α1 (1.8-fold), α-SMA (1.8-fold), and Hsp47 (1.2-fold), while it did not effect PAI-1. Conclusion Both LPS and flagellin could exacerbate fibrogenesis in GF mouse liver slices but not
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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1366A CATEGORY INDEX HEPATOLOGY, Oc
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