Inhibition of TXA<sub>2</sub> synthesis with OKY‐046 improves liver preservation by prolonged hypothermic machine perfusion in rats

Xu, Hui; Lee, Charles Y.; Clemens, Mark G.; Zhang, Jian X.

doi:10.1111/j.1440-1746.2007.05061.x

Cited by 4 publications

(5 citation statements)

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“…A number of animal studies have demonstrated that ozagrel is protective against various forms of trauma and disease, including lung injury [23,33], bronchial asthma [22,40] and ischemia/reperfusion-induced organ injury [41,42]. Ozagrel promptly inhibits TXA 2 synthase in vitro and in vivo [31].…”

Section: Discussionmentioning

confidence: 99%

Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

Tomishima

Ishitsuka

Matsumoto³

et al. 2013

BMC Gastroenterol

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BackgroundOverdosed acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) causes severe liver injury. We examined the effects of ozagrel, a selective thromboxane A2 (TXA2) synthase inhibitor, on liver injury induced by APAP overdose in mice.MethodsHepatotoxicity was induced to ICR male mice by an intraperitoneal injection with APAP (330 mg/kg). The effects of ozagrel (200 mg/kg) treatment 30 min after the APAP injection were evaluated with mortality, serum alanine aminotransferase (ALT) levels and hepatic changes, including histopathology, DNA fragmentation, mRNA expression and total glutathione contents. The impact of ozagrel (0.001-1 mg/mL) on cytochrome P450 2E1 (CYP2E1) activity in mouse hepatic microsome was examined. RLC-16 cells, a rat hepatocytes cell line, were exposed to 0.25 mM N-acetyl-p-benzoquinone imine (NAPQI), a hepatotoxic metabolite of APAP. In this model, the cytoprotective effects of ozagrel (1–100 muM) were evaluated by the WST-1 cell viability assay.ResultsOzagel treatment significantly attenuated higher mortality, elevated serum alanine aminotransferase levels, excessive hepatic centrilobular necrosis, hemorrhaging and DNA fragmentation, as well as increase in plasma 2,3-dinor thromboxane B2 levels induced by APAP injection. Ozagrel also inhibited the hepatic expression of cell death-related mRNAs induced by APAP, such as jun oncogene, FBJ osteosarcoma oncogene (fos) and C/EBP homologous protein (chop), but did not suppress B-cell lymphoma 2-like protein11 (bim) expression and hepatic total glutathione depletion. These results show ozagrel can inhibit not all hepatic changes but can reduce the hepatic necrosis. Ozagrel had little impact on CYP2E1 activity involving the NAPQI production. In addition, ozagrel significantly attenuated cell injury induced by NAPQI in RLC-16.ConclusionsWe demonstrate that the TXA2 synthase inhibitor, ozagrel, dramatically alleviates liver injury induced by APAP in mice, and suggest that it is a promising therapeutic candidate for the treatment of APAP-induced liver injury.

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Section: Discussionmentioning

confidence: 99%

Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

Tomishima

Ishitsuka

Matsumoto³

et al. 2013

BMC Gastroenterol

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“…In addition, hepatic ischemia leads to a detrimental metabolic cascade preceded by a decrease in oxidative phosphorylation, leading to ATP depletion, an increase in anaerobic metabolism, hepatocyte acidosis, dysregulation of ATP-dependent ion exchange mechanisms, mitochondrial dysfunction, cellular swelling, and death ( 21 , 22 ). Moreover, damage to the sinusoidal endothelial cells also leads to damage of hepatic microcirculation—moderated by, among others, the release of thromboxane A2, which plays an important role in liver dysfunction after implantation ( 23 ). Although this complex process is still not fully elucidated, it is known that hepatic ischemia is a key determinant in the development of early allograft dysfunction and negative post-transplant outcomes ( 24 ).…”

Section: Importance Of Graft Preservation and Overview Of Dynamic Pre...mentioning

confidence: 99%

“…Previous experimental studies on animal models support this idea. Xu et al ( 23 ) added a specific thromboxane A2 synthase inhibitor to the perfusate during HMP. The authors found that grafts in the study group demonstrated reduced portal pressure during reperfusion, lower lactate dehydrogenase levels in the perfusate, and significant improvement in tissue edema and hepatocellular necrosis ( 23 ).…”

Section: Graft Modification: Possibilities Beyond the Horizonmentioning

confidence: 99%

“…Xu et al ( 23 ) added a specific thromboxane A2 synthase inhibitor to the perfusate during HMP. The authors found that grafts in the study group demonstrated reduced portal pressure during reperfusion, lower lactate dehydrogenase levels in the perfusate, and significant improvement in tissue edema and hepatocellular necrosis ( 23 ). Recently, Schlegel et al implemented their animal model to a clinical setting and evaluated mitochondrial metabolism ( 36 ).…”

Section: Graft Modification: Possibilities Beyond the Horizonmentioning

confidence: 99%

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Comprehensive review of the application of MP and the potential for graft modification

Vargas

Goldaracena

2023

Front. Transplant.

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IntroductionFollowing procurement, the liver graft is exposed to an ischemic period that triggers several pathophysiologic changes in response to oxygen deprivation. Therefore, the goal during organ preservation is to attenuate such response and provide an adequate environment that prepares the graft for its metabolic reactivation following implantation. This has been widely achieved via static cold storage preservation, where the maintenance of the graft using cold preservation solutions reduce its metabolic activity and confer cytoprotection until transplantation. However, despite being the gold standard for organ preservation, static cold storage holds several disadvantages. In addition, the ongoing organ shortage has led to the use of unconventional grafts that could benefit from therapies pre-transplant. Organ preservation via machine perfusion systems appears as a promising solution to address both.MethodsHere, we aim to present a state-of-the-art narrative review regarding liver graft modification options using machine perfusion systems in combination with adjuvant strategies including immunomodulation, gene therapy and pharmacotherapy.ResultsAvailable reports are scarce and mostly on experimental animal models. Most of the literature reflects the use of normothermic or subnormothermic machine perfusion devices given that these particular type of machine allows for a metabolically active organ, and therefore facilitates its modification. Although limited, promising findings in available reports suggest that organ preservation using machine perfusion system when combined with alternative therapies can be feasible and safe strategies for graft modification.DiscussionFurther research on clinical settings are needed to better elucidate the true effect of graft modification pre-transplant on short- and long-term graft and patient survival. There is a long way ahead to develop guidelines and approve these novel therapies for clinical practice. However, the path looks promising.

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“…One of the strategies used in organ transplants to minimize the injury caused by ischemia is hypothermia. It decreases the cellular components degradation, which is essential for cell viability, enzymatic reactions speed and cell death occurrence, also prevents intracellular acidosis [1][2][3] . This cold-induced down regulation of the metabolism protects the graft against reactive species of oxygen, during reperfusion 2, 4 .…”

Section: Introductionmentioning

confidence: 99%

The effect of n-acetylcysteine on hepatic histomorphology during hypothermic preservation

et al. 2014

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. Tutor. Responsible for conception, design, intellectual and scientific content of the study. Final approval of the version to be published. ABSTRACT PURPOSE:To evaluate the NAC effects on liver hypothermic preservation at different time intervals. METHODS:For this, we used livers of male Wistar rats weighing between 250 and 300g, undergoing preservation in Ringer solution at 4°C for up to 24 hours. Tissue samples were obtained at four moments of preservation for histological examination by hematoxylin and eosin staining: T0 = beginning of preservation, T12 = 12 hours, T18 = 18 hours and T24 = 24 hours. Will be analyzed vacuolation, hepatic apoptosis by optical microscopy and parenchymal. RESULTS:The results showed a progressive increase in hepatic injury in both groups and showed that NAC was effective at T0. The parenchyma preservation was better in the NAC group and no difference when vacuolization of the cells. CONCLUSION:Hypothermic preservation, over time, causes changes in the hepatic parenchyma with increased apoptosis, loss of architecture, vacuolization, culminating in severe injury. The administration of N-acetylcysteine protects against preservation liver injury.

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Inhibition of TXA₂ synthesis with OKY‐046 improves liver preservation by prolonged hypothermic machine perfusion in rats

Abstract: The results demonstrate that TXA(2) is involved in the development of hepatocellular injury induced by HMP, and inhibition of TXA(2) synthesis during preservation and reperfusion protects liver hepatocytes and sinusoidal endothelial cells from injuries caused by prolonged HMP.

Cited by 4 publications

References 53 publications

Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

Comprehensive review of the application of MP and the potential for graft modification

The effect of n-acetylcysteine on hepatic histomorphology during hypothermic preservation

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Inhibition of TXA2 synthesis with OKY‐046 improves liver preservation by prolonged hypothermic machine perfusion in rats

Abstract: The results demonstrate that TXA(2) is involved in the development of hepatocellular injury induced by HMP, and inhibition of TXA(2) synthesis during preservation and reperfusion protects liver hepatocytes and sinusoidal endothelial cells from injuries caused by prolonged HMP.

Cited by 4 publications

References 53 publications

Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

Comprehensive review of the application of MP and the potential for graft modification

The effect of n-acetylcysteine on hepatic histomorphology during hypothermic preservation

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Inhibition of TXA₂ synthesis with OKY‐046 improves liver preservation by prolonged hypothermic machine perfusion in rats