studies

808A AASLD ABSTRACTS HEPATOLOGY, October, 2015
1209
The Small Molecule TLR9 Antagonist COV08-0064
Protects from Warm Ischemia Reperfusion Injury of the
Liver
Mohamed E. Shaker 1,2 , Bobby N. Trawick 3 , Wajahat Z. Mehal 1 ;
1 Section of Digestive Diseases, Yale School of Medicine, New
Haven, CT; 2 Department of Pharmacology & Toxicology, Faculty of
Pharmacy, Mansoura University, Mansoura 35516, Egypt; 3 Center
for Organic Chemistry, Mallinckrodt Pharmaceuticals, St. Louis,
MO
Warm ischemia/reperfusion (IR) injury is a major reason for
failure of liver surgeries, and also limits the use of steatotic livers
for transplantation. A significant portion of the tissue injury
in IR is mediated by activation of an innate immune response
upon reperfusion. Minimizing this innate immune response is an
attractive goal to limit IR injury. Here, we present a novel and
selective small molecule Toll-like receptor (TLR9) antagonist with
the ability to protect from IR injury. Methods: Male C57Bl/6
mice (8-10 weeks) were subjected to 1h of warm hepatic ischemia
by occlusion of the vasculature supplying the left and
median lobes of the liver. Control mice had the same surgical
procedure, but without interruption of liver blood flow. COV08-
0064 was administered at a dose of 80 mg/kg intraperitoneally
1h prior starting ischemia. At 3 h and 12 h after resuming
blood flow, the livers were examined by standard histology,
scored for injury, and qPCR for pro- and anti-inflammatory cytokines
performed. The ability of COV08-0064 to regulate inflammatory
cytokine production was also tested in vitro on mouse
macrophages and plasmacytoid dendritic cells (pDCs). Results:
COV08-0064 pretreatment for I/R-mice resulted in limiting the
rise in serum alanine aminotransferase activity (595 ± 124 vs
3233 ± 785, P