apoptosis in N-acetyl-p-aminophenol-induced liver injury in mice is tissue factor dependent

다국어 초록 (Multilingual Abstract)

Tissue factor (TF) activates the coagulation system and has an important role in the pathogenesis of various diseases. Our previous study stated that retinoid receptors (RAR-α and RXR-α) are released as a lipid droplet in monocrotaline/ lipopolysaccharide-induced idiosyncratic liver toxicity in mice. Herein, the interdependence between the release of retinoid receptors RAR-α and RXR-α and TF in Nacetyl- p-aminophenol (APAP)-induced mice liver toxicity, is investigated. Serum alanine transaminase (ALT) level, platelet and white blood cells (WBCs) counts, protein expression of fibrin, TF, cyclin D1 and cleaved caspase-3 in liver tissues are analyzed. In addition, histopathological evaluation and survival study are also performed. The results indicate that using of TF-antisense (TF-AS) deoxyoligonucleotide (ODN) injection (6 mg/kg), to block TF protein synthesis, significantly restores the elevated level of ALT and WBCs and corrects thrombocytopenia in mice injected with APAP. TF-AS prevents the peri-central overexpression of liver TF, fibrin, cyclin D1 and cleaved caspase- 3. The release of RXR-α and RAR-α droplets, in APAP treated sections, is inhibited upon treatment with TF-AS. In conclusion, the above findings designate that the released RXR-α and RAR-α in APAP liver toxicity is TF dependent. Additionally, the enhancement of cyclin D1 to caspase-3-dependent apoptosis can be prevented by blocking of TF protein synthesis.

목차 (Table of Contents)

• INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS CONFLICTS OF INTEREST

참고문헌 (Reference)

1 Goodman DS, "Vitamin A and retinoids in health and disease" 310 : 1023-1031, 1984

2 Chen Q, "Treatment of acetaminophen-induced liver failure by blocking the death checkpoint protein TRAIL" 1866 : 165583-, 2020

3 Mackman N, "Tissue-specific hemostasis in mice" 25 : 2273-2281, 2005

4 Abdel-Bakky MS, "Tissue factor dependent liver injury causes release of retinoid receptors(RXR-α and RAR-α)as lipid droplets" 410 : 146-151, 2011

5 Hammad MA, "Tissue factor antisense deoxyoligonucleotide prevents monocrotaline/LPS hepatotoxicity in mice" 33 : 774-783, 2013

6 Pearson JM, "The thrombin inhibitor, hirudin, attenuates lipopolysaccharideinduced liver injury in the rat" 278 : 378-383, 1996

7 Bataller R, "Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats" 41 : 1046-1055, 2005

8 Abdel-Bakky MS, "Silencing of tissue factor by antisense deoxyoligonucleotide mitigates thioacetamide-induced liver injury" 393 : 1887-1898, 2020

9 Ganey PE, "Role of the coagulation system in acetaminopheninduced hepatotoxicity in mice" 46 : 1177-1186, 2007

10 Friedman A, "Retinoic acid promotes proliferation and induces expression of retinoic acid receptor-alpha gene in murine T lymphocytes" 152 : 240-248, 1993

11 Gardner CR, "Reduced hepatotoxicity of acetaminophen in mice lacking inducible nitric oxide synthase : potential role of tumor necrosis factor-alpha and interleukin-10" 184 : 27-36, 2002

12 Nagpal S, "Recent developments in receptorselective retinoids" 6 : 919-931, 2000

13 Bhushan B, "Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model" 184 : 3013-3025, 2014

14 Hammad MA, "Oxidized low-density lipoprotein and tissue factor are involved in monocrotaline/lipopolysaccharide-induced hepatotoxicity" 85 : 1079-1089, 2011

15 Brass LF, "Novel therapeutic targets at the platelet vascular interface" 28 : s43-s50, 2008

16 Liu ZX, "Neutrophil depletion protects against murine acetaminophen hepatotoxicity" 43 : 1220-1230, 2006

17 Heestermans M, "Mouse venous thrombosis upon silencing of anticoagulants depends on tissue factor and platelets, not FXII or neutrophils" 133 : 2090-2099, 2019

18 Dragomir AC, "Macrophage activation by factors released from acetaminophen-injured hepatocytes : potential role of HMGB1" 253 : 170-177, 2011

19 Helal MG, "Irbesartan mitigates acute liver injury, oxidative stress, and apoptosis induced by acetaminophen in mice" 34 : e22447-, 2020

20 Mezaki Y, "Insoluble, speckled cytosolic distribution of retinoic acid receptor alpha protein as a marker of hepatic stellate cell activation in vitro" 57 : 687-699, 2009

21 Okuno M, "Increased 9, 13-di-cis-retinoic acid in rat hepatic fibrosis : implication for a potential link between retinoid loss and TGF-beta mediated fibrogenesis in vivo" 30 : 1073-1080, 1999

22 Ohata M, "Diminished retinoic acid signaling in hepatic stellate cells in cholestatic liver fibrosis" 272 (272): G589-G596, 1997

23 Bustany S, "Cyclin D1 sensitizes myeloma cells to endoplasmic reticulum stress-mediated apoptosis by activating the unfolded protein response pathway" 15 : 262-, 2015

24 Pohl E, "Classical pathways of gene regulation by retinoids" 637 : 151-173, 2020

25 Qi Guo, "Carnosic acid protects against acetaminophen-induced hepatotoxicity by potentiating Nrf2-mediated antioxidant capacity in mice" 대한약리학회 20 (20): 15-23, 2016

26 Arai M, "Blood coagulation equilibrium in rat liver microcirculation as evaluated by endothelial cell thrombomodulin and macrophage tissue factor" 80 : 113-123, 1995

27 Nakamura K, "Antisense oligonucleotide for tissue factor inhibits hepatic ischemic reperfusion injury" 297 : 433-441, 2002

28 Li J, "Antifibrotic effects of luteolin on hepatic stellate cells and liver fibrosis by targeting AKT/mTOR/p70S6K and TGFβ/Smad signalling pathways" 35 : 1222-1233, 2015

29 Copple BL, "Anticoagulants prevent monocrotaline-induced hepatic parenchymal cell injury but not endothelial cell injury in the rat" 180 : 186-196, 2002

30 James LP, "Acetaminophen-induced hepatotoxicity" 31 : 1499-1506, 2003

31 Wu YL, "Acanthoic acid, a diterpene in Acanthopanax koreanum, protects acetaminophen-induced hepatic toxicity in mice" 17 : 475-479, 2010