Shouman Maha M, Abdelsalam Rania M, Tawfick Mahmoud M, Kenawy Sanaa A, El-Naa Mona M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern Sciences and Arts University (MSA), Giza, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Front Pharmacol. 2021 May 11;12:676608. doi: 10.3389/fphar.2021.676608. eCollection 2021.
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.
组织因子（TF）是一种血液凝固因子，在许多非凝血途径中发挥多种作用，这些途径涉及不同的病理状况，如血管生成、炎症和纤维化形成。凝血和炎症与肝纤维化相互关联，其中蛋白酶激活受体1（PAR1）和Toll样受体4（TLR4）起着关键作用。反义寡脱氧核苷酸是基因表达的强效调节剂。在本研究中，评估了反义TF寡脱氧核苷酸（TFAS）通过抑制TF基因表达来治疗肝纤维化的效果。通过单次腹腔注射N - 二乙基亚硝胺（DEN，200 mg/kg）诱导大鼠肝纤维化，随后每周皮下注射一次四氯化碳（CCl4，3 ml/kg），持续6周。肝纤维化诱导后，肝脏TF表达显著上调，同时肝酶活性和肝脏组织病理学恶化。肝脏中α平滑肌肌动蛋白（α - SMA）和转化生长因子 - 1β（TGF - 1β）表达、肿瘤坏死因子 - α（TNF - α）以及羟脯氨酸含量和胶原蛋白沉积均显著升高。每周皮下注射一次TFAS（2.8 mg/kg），持续6周，阻断TF表达，显著恢复了肝酶活性，改善了组织病理学特征，同时降低了升高的α - SMA、TGF - 1β、TNF - α、羟脯氨酸和胶原蛋白水平。此外，TFAS降低了肝纤维化诱导的PAR1和TLR4的表达。总之，我们报道TFAS阻断TF表达改善了与CCl4 + DEN中毒相关的炎症和纤维化变化。此外，我们探索了TF、PAR1和TLR4在肝纤维化形成中的潜在关联。这些发现提供了一个平台，通过靶向TF表达可介导肝纤维化的恢复。
