Increased Leukotriene C4 Synthesis Accompanied Enhanced Leukotriene C4 Synthase Expression and Activities of Ischemia–Reperfusion-Injured Liver in Rats

Yang, Shu‐Long; Huang, Xin; Chen, Haifei; Xu, Dan; Chen, Lijun; Kong, Yin; Lou, Yijia

doi:10.1016/j.jss.2006.11.009

Cited by 16 publications

(10 citation statements)

References 49 publications

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“…The product of Ltc4s catalyzes the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4, a potent proinflammatory lipid mediator synthesized from arachidonic acid [Uhlig and Wendel,1992; Lam et al,1994]. The mRNA and protein expression of Ltc4s are both up-regulated in response to ischemia-reperfusion injury in hepatocytes and sinusoidal endothelial cells in rat [Yang et al,2007]. In this study, Ltc4s exhibited a dose dependent increase in expression, which might be indicative of the initiation of liver injury at the medium and high doses.…”

Section: Discussionmentioning

confidence: 99%

Hepatic mRNA, microRNA, and miR‐34a‐Target responses in mice after 28 days exposure to doses of benzo(a)pyrene that elicit DNA damage and mutation

Malik

Williams

Lemieux

et al. 2011

Environ and Mol Mutagen

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Benzo(a)pyrene (BaP) is a mutagenic carcinogen that is ubiquitous in our environment. To better understand the toxic effects of BaP and to explore the relationship between toxicity and toxicogenomics profiles, we assessed global mRNA and microRNA (miRNA) expression in Muta™Mouse. Adult male mice were exposed by oral gavage to 25, 50, and 75 mg/kg/day BaP for 28 days. Liver tissue was collected 3 days following the last treatment. Initially, we established that exposure to BaP led to the formation of hepatic DNA adducts and mutations in the lacZ transgene of the Muta™Mouse. We then analyzed hepatic gene expression profiles. Microarray analysis of liver samples revealed 134 differentially expressed transcripts (adjusted P < 0.05; fold changes > 1.5). The mRNAs most affected were involved in xenobiotic metabolism, immune response, and the downstream targets of p53. In this study, we found a significant 2.0 and 3.6-fold increase following exposure to 50 and 75 mg/kg/day BaP, respectively, relative to controls for miR-34a. This miRNA is involved in p53 response. No other significant changes in miRNAs were observed. The protein levels of five experimentally confirmed miR-34a targets were examined, and no major down-regulation was present. The results suggest that liver miRNAs are largely unresponsive to BaP doses that cause both DNA adducts and mutations. In summary, the validated miRNA and mRNA expression profiles following 28 day BaP exposure reflect a DNA damage response and effects on the cell cycle, consistent with the observed increases in DNA adducts and mutations. Environ. Mol. Mutagen., 2012. © 2011 Crown in the right of Canada

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Section: Discussionmentioning

confidence: 99%

Hepatic mRNA, microRNA, and miR‐34a‐Target responses in mice after 28 days exposure to doses of benzo(a)pyrene that elicit DNA damage and mutation

Malik

Williams

Lemieux

et al. 2011

Environ and Mol Mutagen

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“…21,22 Previous studies provide solid evidence that Cys-LTs have an important role in liver injury. Leukotrienes are involved in different settings of acute liver injury, for example, in hepatic ischemia reperfusion injury, 23 or in the model of endotoxin and D-galactosamine administration leading to liver injury. 5 One postulated mechanism is the activation of chloride conductance in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Role of cysteinyl-leukotrienes for portal pressure regulation and liver damage in cholestatic rat livers

Winkel

Gmelin

Schewe

et al. 2013

Laboratory Investigation

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Kupffer cells (KCs) have a major role in liver injury, and cysteinyl-leukotrienes (Cys-LTs) are known to be involved as well. The KC-mediated pathways for the production and secretion of Cys-LT in cholestatic liver injury have not yet been elucidated. Here, we hypothesized that KC activation by Toll-like receptor ligands results in Cys-LT-mediated microcirculatory alterations and liver injury in acute cholestasis. We hypothesized further that this situation is associated with changes in the secretion and production of Cys-LT. One week after bile duct ligation (BDL), livers showed typical histological signs of cholestatic liver injury. Associated microcirculatory disturbances caused increased basal and maximal portal pressure following KC activation. These differences were determined in BDL livers compared with shamoperated livers in vivo (KC activation by LPS 4 mg/kg b.w.) and in isolated perfused organs (KC activation by Zymosan A, 150 mg/ml). Treatment with the 5-lipoxygenase inhibitor MK-886 alone did not alter portal perfusion pressure, lactate dehydrogenase (LDH) efflux, or bile duct proliferation in BDL animals. Following KC activation, portal perfusion pressure increased. The degree of cell injury was attenuated by MK-886 (3 mM) treatment as estimated by LDH efflux. In normal rats, a large amount of Cys-LT efflux was found in the bile. Only a minor amount was found in the effluent perfusate. In BDL livers, the KC-mediated Cys-LT efflux into the sinusoidal system increased, although the absolute Cys-LT level was still grossly lower than the biliary excretion in sham-operated livers. In conclusion, our results indicate that treatment with Cys-LT inhibitors might be a relevant target for attenuating cholestatic liver damage.

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“…In particular, a 4-to 5-fold increase of the cysLTs content in the hepatic tissue after 12 and 24 h reperfusion, accompanied by the enhancement of hepatic edema and plasma ALT elevation, has been observed [148]. According to recent findings LTC 4 accumulation in rat liver subjected to I/R may be partially caused by up-regulation of LTC 4 S expression and by the increase of LTC 4 synthesis enzyme and/or activities [149]. However, since the pathophysiology of hepatic I/R injury is so complicated, it is essential to further study the mechanisms responsible for LTC 4 accumulation in hepatic I/R injured rats [149].…”

Section: Leukotrienes and Hepatic I/r Injurymentioning

confidence: 93%

“…According to recent findings LTC 4 accumulation in rat liver subjected to I/R may be partially caused by up-regulation of LTC 4 S expression and by the increase of LTC 4 synthesis enzyme and/or activities [149]. However, since the pathophysiology of hepatic I/R injury is so complicated, it is essential to further study the mechanisms responsible for LTC 4 accumulation in hepatic I/R injured rats [149].…”

Section: Leukotrienes and Hepatic I/r Injurymentioning

confidence: 99%

Involvement of Leukotriene Pathway in the Pathogenesis of Ischemia- Reperfusion Injury and Septic and Non-Septic Shock

Rossi¹,

Cuzzocrea²,

Sautebin³

2009

CVP

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The 5-lipoxygenase (5-LO) pathway is responsible for the production of leukotrienes (LTs), inflammatory lipid mediators which play a role in innate immunity. More recently, a pivotal role of LTs in ischemia-reperfusion and shock injury has been suggested. In fact, these pathological conditions are characterized by a severe neutrophil infiltration that gives rise to tissue injury and 5-LO metabolites control neutrophil recruitment in injured tissue by the modulation of adhesion molecule expression. The aim of this review is to analyze the results reported in the literature on the role of 5-LO pathway, with particular regard to LTs, in these pathological conditions. A better understanding of the mechanisms underlying the role of the 5-LO enzyme and/or its metabolites in the regulation of neutrophil trafficking, might open new perspectives in the therapy of organ dysfunction and/or injury associated with shock and ischemia-reperfusion injury.

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Increased Leukotriene C4 Synthesis Accompanied Enhanced Leukotriene C4 Synthase Expression and Activities of Ischemia–Reperfusion-Injured Liver in Rats

Cited by 16 publications

References 49 publications

Hepatic mRNA, microRNA, and miR‐34a‐Target responses in mice after 28 days exposure to doses of benzo(a)pyrene that elicit DNA damage and mutation

Hepatic mRNA, microRNA, and miR‐34a‐Target responses in mice after 28 days exposure to doses of benzo(a)pyrene that elicit DNA damage and mutation

Role of cysteinyl-leukotrienes for portal pressure regulation and liver damage in cholestatic rat livers

Involvement of Leukotriene Pathway in the Pathogenesis of Ischemia- Reperfusion Injury and Septic and Non-Septic Shock

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