Antithrombin reduces ischemia/reperfusion-induced liver injury in rats by activation of cyclooxygenase-1

2004 ◽  
Vol 92 (09) ◽  
pp. 550-558 ◽  
Author(s):  
Naoaki Harada ◽  
Mitsuhiro Uchiba ◽  
Shigeki Kushimoto ◽  
Hirotaka Isobe ◽  
Kenji Okajima
Keyword(s):  
Liver Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Selective Inhibitor ◽  
Hepatic Tissue ◽  
Tissue Blood Flow ◽  
Mrna Levels ◽  
Tissue Levels ◽  
Cox 2 ◽  
Cox 1

SummaryThis study was conducted to determine which isoform of cyclooxygenase (COX) is more significantly involved in the antithrombin (AT)-induced increase in prostaglandin production in the liver of rats, subjected to hepatic ischemia/reperfusion (I/R). Hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of prostacyclin (PGI2), and PGE2 were transiently increased 1 hour after reperfusion. Thereafter, hepatic PGE2 levels were gradually increased until 6 hours after reperfusion, while hepatic 6-keto-PGF1α levels were decreased to the pre-ischemia levels at 6 hours after reperfusion. AT significantly enhanced increases in hepatic tissue levels of 6-keto-PGF1α and PGE2 seen 1 hour after reperfusion, while it inhibited increases in hepatic PGE2 levels seen 6 h after reperfusion. Neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT which lacks affinity for heparin, showed any effects on these changes. Pretreatment with indomethacin (IM), a non-selective inhibitor of COX, inhibited AT-induced increases in hepatic tissue levels of 6-keto-PGF1α and PGE2 seen 1 hour after reperfusion, whereas pretreatment with NS-398, a selective inhibitor of COX-2, did not. The increase in hepatic tissue blood flow and inhibition of hepatic inflammatory responses seen in animals given AT were reversed by pretreatment with IM, but were not affected by pretreatment with NS-398. Administration of iloprost, a stable analog of PGI2, and PGE2 produced effects similar to those induced by AT. Increases in hepatic tissue levels of PGE2 6 hours after reperfusion were inhibited by pretreatment with NS-398. Although AT did not affect COX-1 mRNA levels 1 hour after reperfusion, it inhibited the I/R-induced increases in hepatic tissue levels of both PGE2 and COX-2 mRNA 6 hours after reperfusion. These observations strongly suggested that AT might reduce the I/R-induced liver injury by increasing the production of PGI2 and PGE2 through activation of COX-1. Furthermore, since TNF-a is capable of inducing COX-2, inhibition of TNF-a production by AT might inhibit COX-2-mediated PGE2 production. These effects induced by AT might contribute to its anti-inflammatory activity.

Contribution of capsaicin-sensitive sensory neurons to antithrombin-induced reduction of ischemia/reperfusion-induced liver injury in rats

2005 ◽  
Vol 93 (01) ◽  
pp. 48-56 ◽  
Author(s):  
Naoaki Harada ◽  
Mehtap Yuksel ◽  
Hirotaka Isobe ◽  
Kenji Okajima
Keyword(s):  
Liver Injury ◽  
Sensory Neurons ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Dorsal Root Ganglion Neurons ◽  
Hepatic Tissue ◽  
Tissue Blood Flow ◽  
Tissue Levels ◽  
Neuron Activation ◽  
Ganglion Neurons

SummaryWe previously reported that antithrombin (AT) reduced ischemia/ reperfusion (I/R)-induced liver injury in rats by increasing endothelial production of prostacyclin (PGI2). However, the mechanism(s) underlying this phenomenon remains to be fully elucidated. We also demonstrated that activation of capsaicinsensitive sensory neurons increased endothelial production of PGI2 by releasing calcitonin gene-related peptide (CGRP) in rats subjected to hepatic I/R. In the present study, we investigated whether AT increases endothelial production of PGI2 through activation of the sensory neurons in rats subjected to hepatic I/R. AT significantly enhanced the I/R-induced increases in hepatic tissue levels of CGRP in rats. Increases in hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2 , the increase in hepatic-tissue blood flow, and attenuation of both hepatic local inflammatory responses and liver injury in rats administered AT were completely reversed by administration of capsazepine, an inhibitor of sensory neuron activation and CGRP(8–37), a CGRP antagonist.AT did not show any protective effect on liver injury in animals undergoing functional denervation by administration of a large amount of capsaicin.AT significantly increased CGRP release from cultured dorsal root ganglion neurons isolated from rats in the presence of capsaicin.Taken together,these observations strongly suggested that AT might increase hepatic tissue levels of PGI2 via enhancement of hepatic I/R-induced activation of capsaicin-sensitive sensory neurons,thereby reducing liver injury in rats. In this process, CGRP-induced activation of both endothelial nitric oxide synthase and cyclooxygenase-1 might be critically involved.

Neutrophil elastase contributes to the development of ischemia-reperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats

2004 ◽  
Vol 287 (6) ◽  
pp. G1116-G1123 ◽  
Author(s):  
Kenji Okajima ◽  
Naoaki Harada ◽  
Mitsuhiro Uchiba ◽  
Masakazu Mori
Keyword(s):  
Blood Flow ◽  
Liver Injury ◽  
Neutrophil Elastase ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Hepatic Tissue ◽  
Tissue Blood Flow ◽  
Protective Effects ◽  
Tissue Levels ◽  
Hepatic Tissue Blood Flow

We previously reported that nitric oxide (NO) derived from endothelial NO synthase (NOS) increased endothelial prostacyclin (PGI2) production in rats subjected to hepatic ischemia-reperfusion (I/R). The present study was undertaken to determine whether neutrophil elastase (NE) decreases endothelial production of PGI2, thereby contributing to the development of I/R-induced liver injury by decreasing hepatic tissue blood flow in rats. Hepatic tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2, were transiently increased and peaked at 1 h after reperfusion, followed by a gradual decrease until 3 h after reperfusion. Sivelestat sodium hydrochloride and L-658,758, two NE inhibitors, reduced I/R-induced liver injury. These substances inhibited the decreases in hepatic tissue levels of 6-keto-PGF1αat 2 and 3 h after reperfusion but did not affect the levels at 1 h after reperfusion. These NE inhibitors significantly increased hepatic tissue blood flow from 1 to 3 h after reperfusion. Both hepatic I/R-induced increases in the accumulation of neutrophils and the microvascular permeability were inhibited by these two NE inhibitors. Protective effects induced by the two NE inhibitors were completely reversed by pretreatment with nitro-l-arginine methyl ester, an inhibitor of NOS, or indomethacin. Administration of iloprost, a stable derivative of PGI2, produced effects similar to those induced by NE inhibitors. These observations strongly suggest that NE might play a critical role in the development of I/R-induced liver injury by decreasing endothelial production of NO and PGI2, leading to a decrease in hepatic tissue blood flow resulting from inhibition of vasodilation and induction of activated neutrophil-induced microvascular injury.

Ischemia-reperfusion rapidly increases COX-2 expression in piglet cerebral arteries

1999 ◽  
Vol 277 (3) ◽  
pp. H1207-H1214 ◽  
Author(s):  
Ferenc Domoki ◽  
Roland Veltkamp ◽  
Nishadi Thrikawala ◽  
Greg Robins ◽  
Ferenc Bari ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Cerebral Arteries ◽  
Rnase Protection Assay ◽  
Immunoblot Analysis ◽  
Mrna Levels ◽  
Rnase Protection ◽  
Time Control ◽  
Cox 2 ◽  
Cox 1 ◽  
Ischemic Stress

In the newborn, cyclooxygenase (COX)-derived products play an important role in the cerebrovascular dysfunction after ischemia-reperfusion (I/R). We examined effects of I/R on expression of COX-1 and COX-2 isoforms in large cerebral arteries of anesthetized piglets. The circle of Willis, the basilar, and the middle cerebral arteries were collected from piglets at 0.5–12 h after global ischemia (2.5–10 min, n = 50), hypoxia ( n = 3), or hypercapnia ( n = 2) and from time-control ( n = 19) or untreated animals ( n = 7). Tissues were analyzed for COX-1 and COX-2 mRNA and protein using RNase protection assay and immunoblot analysis, respectively. Ischemia increased COX-2 mRNA by 30 min, and maximal levels were reached at 2 h. Hypoxia or hypercapnia had minimal effects on COX-2 mRNA. COX-2 protein levels were also consistently elevated by 8 h after I/R. Increases in COX-2 mRNA or protein were not influenced by pretreatment with either indomethacin (5 mg/kg iv, n = 5) or nitro-l-arginine methyl ester (15 mg/kg iv, n = 7). COX-1 mRNA levels were low in time controls, and ischemic stress had no significant effect on COX-1 expression. Thus ischemic stress leads to relatively rapid, selective induction of COX-2 in cerebral arteries.

Danaparoid sodium reduces ischemia/reperfusion-induced liver injury in rats by attenuating inflammatory responses

2007 ◽  
Vol 97 (01) ◽  
pp. 81-87 ◽  
Author(s):  
Naoaki Harada ◽  
Hidefumi Kohmura ◽  
Mitsuhiro Uchiba ◽  
Tsutomu Tomita ◽  
Kenji Okajima
Keyword(s):  
Liver Injury ◽  
Rat Model ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Hepatic Tissue ◽  
Therapeutic Effects ◽  
Danaparoid Sodium ◽  
Cgrp Release ◽  
Neuron Activation

SummaryThis study was undertaken to examine the mechanism by which danaparoid sodium (DS), a heparinoid that contains mainly heparan sulfate, prevents reperfusion-induced hepatic damage in a rat model of ischemia/reperfusion (I/R)-induced liver injury. Administration of DS significantly reduced liver injury and inhibited the decrease in hepatic tissue blood flow in rats. DS attenuated hepatic I/R-induced increases in hepatic tissue levels of tumor necrosis factor (TNF) and myeloperoxidase (MPO) in vivo. In contrast, neither monocytic TNF production nor neutrophil activation was inhibited by DS in vitro. DS enhanced I/R-induced increases in levels of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory neurons, and of 6-ketoprostaglandin (PG) F1α, a stable metabolite of PGI2, in liver tissues. The therapeutic effects of DS were not seen in animals pretreated with capsazepine, an inhibitor of sensory neuron activation. The distribution of heparan sulfate in the perivascular area was significantly increased by DS administration in this rat model. DS significantly increased CGRP release from isolated rat dorsal root ganglion neurons (DRG) in vitro, while DX-9065a, a selective inhibitor of activated factor X, did not. DS enhanced anandamide-induced CGRP release from DRG in vitro. These observations strongly suggested that DS might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects of DS might be at least partly explained by its enhancement of sensory neuron activation, leading to the increase the endothelial production of PGI2.

Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation

2006 ◽  
Vol 95 (05) ◽  
pp. 788-795 ◽  
Author(s):  
Naoaki Harada ◽  
Mitsuhiro Uchiba ◽  
Hiroki Kurihara ◽  
Naomi Nakagata ◽  
Kenji Okajima
Keyword(s):  
Liver Injury ◽  
Sensory Neuron ◽  
Sensory Neurons ◽  
Ischemia Reperfusion ◽  
Dorsal Root Ganglion Neurons ◽  
Hepatic Tissue ◽  
Tissue Levels ◽  
Cgrp Release ◽  
Neuron Activation ◽  
Ganglion Neurons

SummaryWe recently demonstrated that antithrombin (AT) reduces ischemia/reperfusion (I/R)-induced liver injury in rats by increasing hepatic tissue levels of calcitonin gene-related peptide (CGRP),a neuropeptide released from the sensory nerve endings. In the present study, we examined the effect of AT on I/Rinduced liver injury in wild type mice (CGRP+/+) and congenitally αCGRP-deficient mice (CGRP−/−). We also investigated any effects of AT on CGRP release from dorsal root ganglion neurons (DRG) isolated from CGRP+/+. Based on results obtained in the present study, we attempted to determine if the anti-inflammatory activity of AT in vivo is dependent mainly on sensory neuron activation. AT enhanced ischemia/reperfusion-induced increases in hepatic tissue levels of CGRP and 6-keto-PGF1α , a stable metabolite of PGI2, in CGRP+/+, but it did not enhance these increases in CGRP−/−. AT inhibited reperfusion-induced increases in serum alanine aminotransferase levels by increasing hepatic tissue blood flow and by attenuating increases in hepatic levels of tumor necrosis factor and myeloperoxidase in CGRP+/+,although it showed neither of these therapeutic effects in CGRP−/−. AT increased CGRP release from cultured DRGs only in the presence of anandamide, and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (PKA).AT markedly increased intracellular levels of cAMP in the presence of anandamide. These results strongly suggest that AT might reduce I/R-induced liver injury by enhancing activation of the sensory neurons through activation of PKA in sensory neurons.

Role of Microthrombus Formation in the Development of Ischemia/Reperfusion-induced Liver Injury in Rats

2002 ◽  
Vol 88 (09) ◽  
pp. 473-480 ◽  
Author(s):  
Naoaki Harada ◽  
Shigeki Kushimoto ◽  
Mitsuhiro Uchiba ◽  
Kenji Okajima
Keyword(s):  
Blood Flow ◽  
Liver Injury ◽  
Neutrophil Elastase ◽  
Ischemia Reperfusion ◽  
Hepatic Tissue ◽  
Tissue Blood Flow ◽  
Therapeutic Effects ◽  
Tnf Α ◽  
Hepatic Tissue Blood Flow

SummaryAlthough tumor necrosis factor-α (TNF-α) has been shown to play a critical role in the pathologic process leading to ischemia/reperfusion (I/R)-induced liver injury in rats by activating neutrophils, it is not clear whether or not microthrombus formation induced by TNF-α contributes to the liver injury. In the present study, we investigated the role of microthrombus formation in I/R-induced liver injury in rats. Hepatic tissue levels of TNF-α were significantly increased after reperfusion, and these were higher in animals subjected to 120 min-hepatic I/R than in those subjected to 60 min-hepatic I/R. Fibrin deposition was observed histologically in the hepatic sinusoidal space only in animals subjected to 120 min-hepatic I/R. Both the decrease in hepatic tissue blood flow and the extent of liver injury in animals subjected to 60 minand 120 min-hepatic I/R were significantly inhibited by pretreatment with anti-rat TNF-α antibody. Although neutrophil elastase inhibitors inhibited the decrease in hepatic tissue blood flow and reduced liver injury in animals subjected to 60 min-hepatic I/R, anticoagulants did not show any effects. Both anticoagulants and neutrophil elastase inhibitors inhibited the decrease in hepatic tissue blood flow and reduced liver injury in animals subjected to 120 min-hepatic I/R. Therapeutic effects of anti-rat TNF-α antibody on the120 min-I/R-induced liver injury were more marked than those of each anticoagulant or each neutrophil elastase inhibitor, and were comparable to those of combined use of anticoagulants and neutrophil elastase inhibitors. These observations strongly suggest that TNF-α induces I/R-induced liver injury primarily by activating neutrophils, and it exacerbates liver injury by inducing microthrombus formation when the production of TNF-α is further increased.

scholarly journals Maresin 1 protects the liver against ischemia/reperfusion injury via the ALXR/Akt signaling pathway

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Da Tang ◽  
Guang Fu ◽  
Wenbo Li ◽  
Ping Sun ◽  
Patricia A. Loughran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Serum Aminotransferase ◽  
Primary Mouse ◽  
Maresin 1

Abstract Background Hepatic ischemia/reperfusion (I/R) injury can be a major complication following liver surgery contributing to post-operative liver dysfunction. Maresin 1 (MaR1), a pro-resolving lipid mediator, has been shown to suppress I/R injury. However, the mechanisms that account for the protective effects of MaR1 in I/R injury remain unknown. Methods WT (C57BL/6J) mice were subjected to partial hepatic warm ischemia for 60mins followed by reperfusion. Mice were treated with MaR1 (5-20 ng/mouse), Boc2 (Lipoxin A4 receptor antagonist), LY294002 (Akt inhibitor) or corresponding controls just prior to liver I/R or at the beginning of reperfusion. Blood and liver samples were collected at 6 h post-reperfusion. Serum aminotransferase, histopathologic changes, inflammatory cytokines, and oxidative stress were analyzed to evaluate liver injury. Signaling pathways were also investigated in vitro using primary mouse hepatocyte (HC) cultures to identify underlying mechanisms for MaR1 in liver I/R injury. Results MaR1 treatment significantly reduced ALT and AST levels, diminished necrotic areas, suppressed inflammatory responses, attenuated oxidative stress and decreased hepatocyte apoptosis in liver after I/R. Akt signaling was significantly increased in the MaR1-treated liver I/R group compared with controls. The protective effect of MaR1 was abrogated by pretreatment with Boc2, which together with MaR1-induced Akt activation. MaR1-mediated liver protection was reversed by inhibition of Akt. Conclusions MaR1 protects the liver against hepatic I/R injury via an ALXR/Akt signaling pathway. MaR1 may represent a novel therapeutic agent to mitigate the detrimental effects of I/R-induced liver injury.

scholarly journals Kyungheechunggan-Tang-01, a New Herbal Medication, Suppresses LPS-Induced Inflammatory Responses through JAK/STAT Signaling Pathway in RAW 264.7 Macrophages

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Hee-Soo Han ◽  
Eungyeong Jang ◽  
Ji-Sun Shin ◽  
Kyung-Soo Inn ◽  
Jang-Hoon Lee ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Molecular Data ◽  
Mrna Levels ◽  
Protein Levels ◽  
Stat3 Phosphorylation ◽  
Stat Signaling ◽  
Cox 2 ◽  
Anti Inflammatory

Medicinal plants have been used as alternative therapeutic tools to alleviate inflammatory diseases. The objective of this study was to evaluate anti-inflammatory properties of Kyungheechunggan-tang- (KCT-) 01, KCT-02, and Injinchunggan-tang (IJCGT) as newly developed decoctions containing 3–11 herbs in LPS-induced macrophages. KCT-01 showed the most potent inhibitory effects on LPS-induced NO, PGE2, TNF-α, and IL-6 production among those three herbal formulas. In addition, KCT-01 significantly inhibited LPS-induced iNOS and COX-2 at protein levels and expression of iNOS, COX-2, TNF-α, and IL-6 at mRNA levels. Molecular data revealed that KCT-01 attenuated the activation of JAK/STAT signaling cascade without affecting NF-κB or AP-1 activation. In ear inflammation induced by croton oil, KCT-01 significantly reduced edema, MPO activity, expression levels of iNOS and COX-2, and STAT3 phosphorylation in ear tissues. Taken together, our findings suggest that KCT-01 can downregulate the expression of proinflammatory genes by inhibiting JAK/STAT signaling pathway under inflammatory conditions. This study provides useful data for further exploration and application of KCT-01 as a potential anti-inflammatory medicine.

Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines

2001 ◽  
Vol 281 (6) ◽  
pp. G1348-G1356 ◽  
Author(s):  
Amin A. Nanji ◽  
Kalle Jokelainen ◽  
Maryam Fotouhinia ◽  
Amir Rahemtulla ◽  
Peter Thomas ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Liver Injury ◽  
Fish Oil ◽  
Nonheme Iron ◽  
Female Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Alcoholic Liver Injury ◽  
Tnf Α ◽  
Cox 2

Alcoholic liver injury is more severe and rapidly developing in women than men. To evaluate the reason(s) for these gender-related differences, we determined whether pathogenic mechanisms important in alcoholic liver injury in male rats were further upregulated in female rats. Male and age-matched female rats (7/group) were fed ethanol and a diet containing fish oil for 4 wk by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. We analyzed liver histopathology, lipid peroxidation, cytochrome P-450 (CYP)2E1 activity, nonheme iron, endotoxin, nuclear factor-κB (NF-κB) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). Alcohol-induced liver injury was more severe in female vs. male rats. Female rats had higher endotoxin, lipid peroxidation, and nonheme iron levels and increased NF-κB activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-α and COX-2 levels were similar in male and female rats. Remarkably, female rats fed fish oil and dextrose also showed necrosis and inflammation. Our findings in ethanol-fed rats suggest that increased endotoxemia and lipid peroxidation in females stimulate NF-κB activation and chemokine production, enhancing liver injury. TNF-α and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.

scholarly journals Isoorientin, a Selective Inhibitor of Cyclooxygenase-2 (COX-2) from the Tubers of Pueraria tuberosa

2015 ◽  
Vol 10 (10) ◽  
pp. 1934578X1501001 ◽  
Author(s):  
Manne Sumalatha ◽  
Rachakunta Munikishore ◽  
Aluru Rammohan ◽  
Duvvuru Gunasekar ◽  
Kotha Anil Kumar ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Methanol Extract ◽  
2D Nmr ◽  
Docking Studies ◽  
Selective Inhibitor ◽  
Pueraria Tuberosa ◽  
Nmr Techniques ◽  
Cox 2 ◽  
Plant Sources ◽  
Cox 1

Bioassay-guided fraction of the methanol extract of the roots of Pueraria tuberose DC yielded puerarin, an isoflavone C-glycoside (PT-1), isoorientin, a flavone C-glycoside (PT-2) and mangiferin, a xanthone C-glycoside (PT-3). The extracts and the isolated compounds were screened for potent antiinflammatory components inhibiting the cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX), the target enzymes of inflammation, by employing spectroscopic/polorographic methods. Among these, isoorientin was found to be a potent inhibitorof COX-2with an IC50 value of 39 μM. Docking studies were carried out to understand the interactions of isorientin (PT-2) with COX-2. The structures of the isolates were determined by mass spectrometry and 2D-NMR techniques including HSQC, HMBC, NOESY and 1H-1H COSY experiments. Although isoorientin and mangiferin have been reported from several plant sources, this is the first report of their isolation from a Pueraria species.

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