title: Tissue factor antisense deoxyoligonucleotide prevents monocrotaline/LPS hepatotoxicity in mice.
abstract: Tissue factor (TF) is a membranous glycoprotein that functions as a receptor for coagulation factor VII/VIIa and activates the coagulation system when blood vessels or tissues are damaged. TF was upregulated in our monocrotaline (MCT)/lipopolysaccharide (LPS) hepatotoxicity model. We tested the hypothesis that TF-dependent fibrin deposition and lipid peroxidation in the form of oxidized low-density-lipoprotein (ox-LDL) accumulation contribute to liver inflammation induced by MCT/LPS in mice. In the present study, we blocked TF using antisense oligodeoxynucleotides against mouse TF (TF-ASO). TF-ASO (5.6 mg kg(-1) ) was given i.v. to ND4 male mice 30 min after administration of MCT (200 mg kg(-1) ) p.o. followed after 3.5 h by LPS i.p. (6 mg kg(-1) ). Blood alanine aminotransferase (ALT), TF, ox-LDL, platelets, hematocrit and keratinocyte-derived chemokine (KC) levels were evaluated in different treatment groups. Fibrin deposition and ox-LDL accumulation were also analyzed in the liver sections using immunofluorescent staining. The results showed that TF-ASO significantly restored blood ALT, hematocrit and KC levels, distorted after MCT/LPS co-treatment, as well as preventing the accumulation of ox-LDL and the deposition of fibrin in the liver tissues, and thereby inhibited liver injury caused by MCT/LPS. In a separate experiment, TF-ASO administration significantly prolonged animal survival. The current study demonstrates that TF is associated with MCT/LPS-induced liver injury. Administration of TF-ASO successfully prevented this type of liver injury.
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Hammad
authors.forename: Mohamed Sadek
authors.initials: MS
authors.lastname: Abdel-Bakky
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Ashfaq
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001777:Blood Coagulation; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D006400:Hematocrit; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity*; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D016686:Monocrotaline / Q000633:toxicity*; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*
chemical_list: D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D016376:Oligonucleotides, Antisense; C099252:oxidized low density lipoprotein; C074302:keratinocyte-derived chemokines; D016686:Monocrotaline; D013925:Thromboplastin; D000410:Alanine Transaminase