Oxygen-derived free radicals promote hepatic injury in the rat

Arthur, M. J. P.; Bentley, I.S.; Tanner, A R; Saunders, P.Kowalski; Millward-Sadler, G. H.; Wright, Ralph

doi:10.1016/0016-5085(85)90218-5

Cited by 188 publications

(77 citation statements)

References 17 publications

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“…TNF-α is a multifunctional cytokine secreted by activated macrophages, monocytes, neutrophils and NK-cells. In addition to its direct cytotoxic effects, it is able to induce chemokines, macrophage chemotactic protein-1 and vascular cell adhesion molecule-1, which are the key to hyper inflammation and consequent liver damage [45][46][47][48]. Cellular sensitivity or resistance to TNF-α is correlated with decreased or increased levels of SOD respectively [49][50][51].…”

Section: Discussionmentioning

confidence: 99%

Vitamin E Supplementation Modulates Endotoxin-induced Liver Damage in a Rat Model

Bharrhan¹,

Chopra²,

Rishi³

2010

Am. J. Biomed. Sci.

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Vitamin E (-Tocopherol [-Toc]) is the primary membrane bound, lipid-soluble, chain-breaking antioxidant that has been reported to protect against lipid peroxidation-induced tissue damage. Therefore, the present study was designed to investigate the protection afforded by α-Tocopherol (vitamin E), if any, on LPS-induced liver injury in Wistar rats and to study the underlying mechanism of protection. Bacterial endotoxin (10 mg/Kg body weight-prestandardized dose) was injected intraperitoneally and animals were sacrificed 8 h post-challenge. Vitamin E (35 mg/Kg body weight) was administered orally for 15 days prior to endotoxin challenge. Challenge with LPS resulted in a significant increase in the activities of serum transaminases and alkaline phosphatase along with histological alterations in the liver. These responses were associated with elevated levels of malondialdehyde (MDA) and reduced levels of glutathione, superoxide dismutase and catalase along with increased levels of tumor necrosis factor alpha (TNF-α) in the liver homogenates. However, vitamin E supplementation attenuated the oxidative stress by reducing the levels of MDA, restoring the levels of glutathione, superoxide dismutase and catalase and decreasing the levels of TNF-α. Decreased TNF-α levels after vitamin E supplementation might have resulted into the modulation of above mentioned biochemical changes resulting into amelioration of hepatic architecture. Vitamin E, therefore, seems to have a promising role for clinical manifestations due to oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Vitamin E Supplementation Modulates Endotoxin-induced Liver Damage in a Rat Model

Bharrhan¹,

Chopra²,

Rishi³

2010

Am. J. Biomed. Sci.

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“…There is an initial acute phase characterized by hepatocellular damage at 3 to 6 hours, and a subacute phase characterized by massive neutrophil infiltration at 18 to 24 hours. 4,5 The mechanisms of liver damage following I/R are thought to involve a complex interaction of acute cellular damage caused by ROS, 6,7 detrimental cellular responses resulting from tumor necrosis factor ␣ and interleukin-1 released by Kupffer cells , and subacute leukocyte recruitment that further exacerbates liver injury. 4,8,9,10 Numerous studies suggest that oxygen-free radical formation following reoxygenation may initiate the cascade of hepatocellular injury, necrosis/apoptosis, and subsequent inflammatory infiltration.…”

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confidence: 99%

“…4,8,9,10 Numerous studies suggest that oxygen-free radical formation following reoxygenation may initiate the cascade of hepatocellular injury, necrosis/apoptosis, and subsequent inflammatory infiltration. 6,[11][12][13] Free radicals produced following I/R can lead to oxidative damage of DNA, proteins, and lipids, which contribute to cellular dysfunction or can directly regulate signal transduction. All of these redox-sensitive pathways can ultimately affect liver remodeling following injury through the production of cytokines and growth factors.…”

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confidence: 99%

Subcellular Site of Superoxide Dismutase Expression Differentially Controls Ap–1 Activity and Injury in Mouse Liver Following Ischemia/Reperfusion

et al. 2001

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The cellular redox state has been increasingly recognized as a critical component of stress-induced cellular responses and disease. Inherent in these responses are reactive oxygen species (ROS), including • O 2 Ϫ , H 2 O 2 , and • OH, which inflict direct cellular damage in addition to acting as intracellular second messengers modulating signal transduction pathways. These intracellular highways of communication are critical in determining cell fates and whole-organ responses following environmental injury. Pathologic events caused by transient tissue hypoxia followed by oxygen reperfusion (ischemic/reperfusion [I/R]) are the cause of numerous types of surgical and environmentally induced injuries in the liver associated with transplantation and resection. Pathologic changes encountered following reperfusion of an ischemic organ include the immediate generation of ROS, as well as subsequent neutrophil-predominant inflammatory responses that lead to a second round of deleterious ROS generation at sites of damage. Recently, it has become increasingly appreciated that ROS are involved as second messengers in a number of cellular signaling events leading to the induction of AP-1 and nuclear factor-B pathways.

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“…7 In the P. acnes model, activated hepatic macrophages after endotoxin stimulation destroyed sinusoidal endothelial cells by releasing superoxide anions and tumor necrosis factor ␣ and provoked fibrin deposition in the hepatic sinusoids. 2,5,6,[8][9][10] Such mechanisms, however, may not be involved in the development of sinusoidal fibrin deposition in the partialhepatectomy model, because polyclonal antibody against tumor necrosis factor ␣ and superoxide anion dismutase were ineffective for attenuation of the liver injury. 3,6 Moreover, selective eradication of large hepatic macrophages responsible for production of cytotoxic mediators using gadolinium chloride 11 significantly attenuated liver injury in the P. acnes model, but not liver injury in the partial-hepatectomy model, 5,6 whereas suppression of activation of Kupffer cells and hepatic macrophages by pretreatment of gum arabic 12 produced similar attenuation of liver injuries in both models.…”

mentioning

confidence: 99%

Deranged Blood Coagulation Equilibrium As A Factor of Massive Liver Necrosis Following Endotoxin Administration in Partially Hepatectomized Rats

et al. 1999

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Activated Kupffer cells provoke massive liver necrosis after endotoxin stimulation through microcirculatory disturbance caused by sinusoidal fibrin deposition in rats undergoing 70% hepatectomy. In these rats, serum activities of purine nucleoside phosphorylase (PNP) and alanine transaminase (ALT) were increased at 1 and 5 hours, respectively, following endotoxin administration. When 70% resected liver was perfused with Dulbecco's modified Eagle medium (DMEM) containing heat-inactivated fetal calf serum, the increase in both enzyme activities was not affected by addition of endotoxin during perfusion, suggesting that activated Kupffer cells injured neither sinusoidal endothelial cells nor hepatocytes. The activity of tissue factor, an initiator of blood coagulation cascade, was much higher in Kupffer cells isolated from partially hepatectomized rats than in those from normal rats. In contrast, mRNA expressions of tissue factor pathway inhibitor (TFPI) as well as thrombomodulin were almost undetectable in normal and partially resected livers. When recombinant human TFPI was injected intravenously in 70% hepatectomized rats, TFPI was markedly stained on the surfaces of sinusoidal endothelial cells and microvilli of hepatocytes on immunohistochemistry. In these rats, endotoxin-induced liver injury was significantly attenuated compared with rats given no TFPI. Similar attenuation was also found in rats receiving recombinant human thrombomodulin. These results suggest that fibrin deposition developing in 70% hepatectomized rats after endotoxin administration may be caused by deranged blood coagulation in the hepatic sinusoids through increasing tissue factor activity in Massive liver necrosis develops after endotoxin administration in rats pretreated with heat-killed Propionibacterium acnes or those undergoing 70% liver resection as a result of microcirculatory disturbance caused by sinusoidal fibrin deposition. [1][2][3] In both models, Kupffer cells and hepatic macrophages are activated to provoke endothelial cell injury and fibrin deposition in the hepatic sinusoids. 2-6 However, an apparent difference exists in the stimulatory state of Kupffer cells and hepatic macrophages between both models, because activated Kupffer cells in the partial-hepatectomy model produced fewer cytotoxic mediators such as superoxide anions and tumor necrosis factor ␣ in response to endotoxin administration compared with activated hepatic macrophages in the P. acnes model, 6,7 although both cells can release a large amount of superoxide anions after stimulation with phorbol 12-myristate 13-acetate. 3,4 Northern blot analysis revealed that such difference resulted from expression of endotoxin receptors on the cells; P. acnes-treated rat liver showed increased mRNA expression of CD14, a receptor for lipopolysaccharide and its binding protein complex, compared with normal liver, while such expression was markedly reduced in partially hepatectomized rat liver. 7 In the P. acnes model, activated hepatic macrophages after endotoxin stimulatio...

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Oxygen-derived free radicals promote hepatic injury in the rat

Cited by 188 publications

References 17 publications

Vitamin E Supplementation Modulates Endotoxin-induced Liver Damage in a Rat Model

Vitamin E Supplementation Modulates Endotoxin-induced Liver Damage in a Rat Model

Subcellular Site of Superoxide Dismutase Expression Differentially Controls Ap–1 Activity and Injury in Mouse Liver Following Ischemia/Reperfusion

Deranged Blood Coagulation Equilibrium As A Factor of Massive Liver Necrosis Following Endotoxin Administration in Partially Hepatectomized Rats

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