studies

954A AASLD ABSTRACTS HEPATOLOGY, October, 2015
HVPG ≥10mmHg (R=0.818, p=0.007). Conclusion We have
demonstrated that parameters related to both hepatic architecture
and splanchnic haemodynamics derived from non-contrast
quantitative MR imaging techniques correlate significantly with
HVPG.
Disclosures:
The following authors have nothing to disclose: Naaventhan Palaniyappan, Eleanor
Cox, Andrew Austin, Indra Neil Guha, Susan Francis, Guruprasad P. Aithal
1525
The soluble guanylyl cyclase stimulator riociguat
reduces liver fibrosis and portal pressure in cirrhotic rats
Philipp Schwabl 1 , Ksenia Brusilovskaya 1 , Florian Riedl 1 , David
J. Bauer 1 , Bastian Strobel 1 , Paul Supper 1 , Hubert Hayden 1 ,
Michael Trauner 1 , Bruno K. Podesser 2 , Katharina Wochner 2 ,
Markus Peck-Radosavljevic 1 , Thomas Reiberger 1 ; 1 Division of Gastroenterology
and Hepatology, Department of Internal Medicine
III, Medical University of Vienna, Vienna, Austria; 2 Department
for Biomedical Research, Medical University of Vienna, Vienna,
Austria
Background: In liver cirrhosis nitric oxide (NO) signaling as
well as the function of its key downstream target soluble guanylyl
cyclase (sGC) is distorted. The sGC stimulator riociguat
(RIO) is used for treatment of pulmonary hypertension. Since
RIO has been shown to have additional antifibrotic activity,
we aimed to investigate effects of RIO in rats with cirrhotic
portal hypertension. Methods: Cirrhosis was induced by carbontetrachloride
injections (CCl4, 8 weeks) or by bile duct ligation
(BDL, 3 weeks) in Sprague Dawley rats. Controls received
olive-oil (OO) or underwent sham operation (SO), respectively.
RIO (1mg/kg/d, gavage) or vehicle (VEH) was administered
from weeks 6-8 in CCl4/OO and from weeks 2-3 in BDL/
SO animals. Mean arterial pressure (MAP), heart rate (HR),
portal pressure (PP) and superior mesenteric artery blood flow
(SMABF) were measured. Porto-systemic and spleno-renal shunting
was assessed by colored microspheres technique. Hepatic
fibrosis was quantified by hepatic hydroxyproline content (HP)
and histology. Results: CCl4 rats presented with marked cirrhosis,
hyperdynamic circulation, portal hypertension and elevated
SMABF compared to OO animals. In CCl4 rats, RIO had no
effect on HR, MAP and PP but significantly decreased SMABF
(74±11 vs. 43±6 mL/min; p=0.036). Further, in CCl4 cirrhosis
RIO significantly decreased spleen (1.3±0.1 vs. 1.0±0.1g;
p=0.008) and liver (16.7±1.2 vs. 11.5±2.4g; p=0.015)
weight. BDL rats presented with hepatosplenomegaly and portal
hypertension. In the BDL model RIO significantly increased
MAP (85±17 vs. 108±14mmHg; p=0.016) and decreased PP
(13.2±2.5 vs. 10.1±2.4; p=0.048), but had no effect on HR,
SMABF or shunting. HP was significantly decreased (286±147
vs. 144±74 μg; p=0.039) in BDL-RIO rats, compared to BDL-
VEH animals. Conclusions: RIO treatment significantly reduced
liver fibrosis and ameliorated hyperdynamic circulation as well
as portal pressure in biliary cirrhosis. In toxic cirrhosis RIO
prevented development of hepatosplenomegaly and reduced
splanchnic blood inflow compared to controls. RIO could be
a good candidate for combination studies with other agents
known to improve hepatic hemodynamics in cirrhosis of various
etiologies.
Disclosures:
Michael Trauner - Advisory Committees or Review Panels: MSD, Janssen, Gilead,
Abbvie; Consulting: Phenex; Grant/Research Support: Intercept, Falk Pharma,
Albireo; Patent Held/Filed: Med Uni Graz (norUDCA); Speaking and Teaching:
Falk Foundation, Roche, Gilead
Markus Peck-Radosavljevic - Advisory Committees or Review Panels: Bayer, Gilead,
Janssen, BMS, AbbVie; Consulting: Bayer, Boehringer-Ingelheim, Jennerex,
Eli Lilly, AbbVie; Grant/Research Support: Bayer, Roche, Gilead, MSD, AbbVie;
Speaking and Teaching: Bayer, Roche, Gilead, MSD, Eli Lilly, AbbVie, Bayer
Thomas Reiberger - Consulting: Xtuit; Grant/Research Support: Roche, Gilead,
MSD, Phenex; Speaking and Teaching: Roche, Gilead, MSD
The following authors have nothing to disclose: Philipp Schwabl, Ksenia Brusilovskaya,
Florian Riedl, David J. Bauer, Bastian Strobel, Paul Supper, Hubert
Hayden, Bruno K. Podesser, Katharina Wochner
1526
Portal tract fibrosis is induced by hepatic arterial buffer
response in portal hypertensive rats: A role for macrophage
miR154 released via exosome
Li Gong 1,2 , Chao Dong 1,3 , Teruo Utsumi 1 , Yasuko Iwakiri 1 ; 1 Internal
Medicine, Section of Digestive Diseases, Yale University School
of Medicine, New Haven, CT; 2 Anesthesiology, The third Xiangya
Hospital, Central South University, Changsha, China; 3 General
Surgery, Xiangya Hospital, Central South University, Changsha,
China
Background: The hepatic arterial buffer response increases
hepatic arterial (HA) flow in response to decreased portal
venous flow in portal hypertension. Hemodynamic stresses
associated with increased HA flow may influence intrahepatic
microenvironments around the HA, including resident fibroblasts
of the portal tract region, portal myofibroblast (PMF),
which is a major contributor to portal tract fibrosis. The relation
between increased HA flow and portal tract fibrosis has
not been determined. We hypothesize that hemodynamic
stresses associated with increased HA flow promote infiltration
of macrophages that modulate PMF function and contribute
to the development of portal tract fibrosis in portal hypertension.
Method: Male Sprague Dawley rats underwent sham
operation or partial portal vein ligation (PPVL) to induce portal
hypertension. Livers were isolated 10 days after the surgery
for histological, immunohistochemical and biochemical analyses.
Microarray analysis was performed to determine changes
in gene profiling between sham and PPVL rats. To examine
exosome transfer from macrophages to PMF, co-culture experiments
were performed using macrophage-rich cell population
isolated from spleens of rats that express green fluorescent
protein (GFP) and PMF of normal rats. Exosomes were verified
by scanning electron microscope, CD63 (an exosome marker),
and nanoparticle tracking analysis. Results: Sirius red staining
of livers determined that portal tract fibrosis significantly
developed in rats 10 days after PPVL (2-fold, p