Antisense Tissue Factor Oligodeoxynucleotides Protected Diethyl Nitrosamine/Carbon Tetrachloride-Induced Liver Fibrosis Through Toll Like Receptor4-Tissue Factor-Protease Activated Receptor1 Pathway
Loading...
Date
05/11/2021
Journal Title
Journal ISSN
Volume Title
Type
Article
Publisher
frontiersin
Series Info
Frontiers in Pharmacology;Volume 12 | Article 676608
Scientific Journal Rankings
Abstract
Tissue factor (TF) is a blood coagulation factor that has several roles in many non-coagulant
pathways involved in different pathological conditions such as angiogenesis, inflammation and
fibrogenesis. Coagulation and inflammation are crosslinked with liver fibrosis where protease-
activated receptor1 (PAR1) and toll-like receptor4 (TLR4) play a key role. Antisense
oligodeoxynucleotides are strong modulators of gene expression. In the present study,
antisense TF oligodeoxynucleotides (TFAS) was evaluated in treating liver fibrosis via
suppression of TF gene expression. Liver fibrosis was induced in rats by a single
administration of N-diethyl nitrosamine (DEN, 200 mg/kg; i. p.) followed by carbon
tetrachloride (CCl4, 3 ml/kg; s. c.) once weekly for 6 weeks. Following fibrosis induction,
liver TF expression was significantly upregulated along with liver enzymes activities and liver
histopathological deterioration. Alpha smooth muscle actin (α-SMA) and transforming growth
factor-1beta (TGF-1β) expression, tumor necrosis factor-alpha (TNF-α) and hydroxyproline
content and collagen deposition were significantly elevated in the liver. Blocking of TF
expression by TFAS injection (2.8 mg/kg; s. c.) once weekly for 6 weeks significantly
restored liver enzymes activities and improved histopathological features along with
decreasing the elevated α-SMA, TGF-1β, TNF-α, hydroxyproline and collagen. Moreover,
TFAS decreased the expression of both PAR1 and TLR4 that were induced by liver fibrosis. In
conclusion, we reported that blockage of TF expression by TFAS improved inflammatory and
fibrotic changes associated with CCl4+DEN intoxication. In addition, we explored the potential
crosslink between the TF, PAR1 and TLR4 in liver fibrogenesis. These findings offer a platform
on which recovery from liver fibrosis could be mediated through targeting TF expression.
Description
Scopus
Keywords
TF, PAR1, TLR4, liver fibrosis, inflammation, antisense oligodeoxynucleotides