Mast Cells Are Not Involved in the Ischemia-Reperfusion Injury in Perfused Rat Liver

Shibamoto, Toshishige; Tsutsumi, Mikihiro; Kuda, Yuhichi; Ohmukai, Chieko; Zhang, Wei; Kurata, Yasutaka

doi:10.1016/j.jss.2010.11.900

Cited by 7 publications

(6 citation statements)

References 20 publications

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“…Further, in rats, ischemic reperfusion has been shown to decrease hepatic bile flow and treatment with ranitidine reversed these effects, again demonstrating that histamine (through HR activation) has a relevant effect on choleresis and hepatic function. Interestingly, a study investigating MC effects on ischemic reperfusion and bile flow found that there was no difference in bile flow excretion between WT rats and MC‐deficient, Ws/Ws rats, which, in contrast to our study, might be explained by the difference in injury and rodent model. Our data demonstrate that hepatic bile flow is increased in PSC mice (which have more MCs compared to WT), and our studies are the first to demonstrate that inhibition of MC‐derived histamine may regulate the bicarbonate umbrella and have a protective role against toxic bile in Mdr2 −/− mice.…”

Section: Discussioncontrasting

confidence: 99%

Inhibition of mast cell‐secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice

et al. 2016

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Background and Aim Hepatic fibrosis is marked by activation of hepatic stellate cells (HSCs). Cholestatic injury precedes liver fibrosis and cholangiocytes interact with HSCs promoting fibrosis. Mast cells (MCs) infiltrate following liver injury and release histamine increasing biliary proliferation. We evaluated if inhibition of MC-derived histamine decreases biliary proliferation and fibrosis. Methods WT and Mdr2−/− mice (9-11 weeks) were treated with cromolyn sodium for 1 week to block MC-derived histamine. Biliary mass and proliferation were evaluated by immunohistochemistry for CK-19 and Ki-67. Bile flow, bicarbonate excretion and total bile acids were measured in all mice. Fibrosis was evaluated by Sirius Red/Fast Green staining and by qPCR for α-SMA, fibronectin, collagen type 1a and TGF-β1. HSC activation was evaluated by qPCR in total liver and immunofluorescent staining in tissues for synaptophysin 9. Histamine serum secretion was measured by EIA. Mouse liver and human liver samples from control or PSC patients were evaluated for MC markers by qPCR and immunohistochemistry. In vitro, cultured MCs were transfected with HDC shRNA to decrease histamine secretion and subsequently co-cultured with cholangiocytes or HSCs prior to measuring fibrosis markers, proliferation and TGF-β1 secretion. Results Treatment with cromolyn sodium decreased biliary proliferation, fibrosis, histamine secretion, and bile flow in Mdr2−/− mice. PSC mice and patients have increased MCs. Knockdown of MC HDC decreased cholangiocyte and HSC proliferation/activation. Conclusion MCs are recruited to proliferating cholangiocytes and promote fibrosis. Inhibition of MC-derived histamine decreases fibrosis and regulation of MC mediators may be a therapeutic for PSC.

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Section: Discussioncontrasting

confidence: 99%

Inhibition of mast cell‐secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice

et al. 2016

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“…In one study, it has been reported that mast cells do not play a role in hepatic I/R injury. However, mast cells may not be seen because this study was performed in vitro, and the data were collected 1 h after reperfusion (58). In another study, it was found that mast cells had an important role in I/R injury, and degranulation of mast cells increased in this injury model (59).…”

Section: Discussionmentioning

confidence: 90%

Cannabinoid receptor type 2 agonist JWH-133 deteriorates the liver toxicity induced by cypermethrin

2018

Turk J Vet Anim Sci

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IntroductionCYP is a synthetic type II pyrethroid insecticide widely used for the control of ectoparasites of domestic animals and home pest control owing to its high insecticidal potential and lower mammalian toxicity (1). CYP shows its effect via the voltage-dependent Na + and Ca 2+ channels in the membrane of nerve cells (2-4). There is an increasing amount of evidence suggesting toxic effects on nontarget organisms in chronic exposure of CYP (5,6). Several studies have shown that CYP causes oxidative stress, biochemical changes such as increase in activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH); elevation in levels of thiobarbituric acid reactive substances (TBARS), a decrease in activities of the antioxidant enzymes (7,8), and histopathological changes such as vacuolar degeneration, enlarged sinusoid, vacuole formation in hepatocytes, pleomorphism in the nucleus, congestion, necrosis, hepatocellular hypertrophy, multinucleated hepatocytes, mononuclear cell infiltration (MCI), and increase in Kupffer cell numbers (2,6).Marijuana or cannabis, whose main active ingredient is delta-9-tetrahydrocannabinol, activates two G proteincoupled membrane receptors, named CB1 and CB2 (9-11). CB1 is mainly expressed in the nervous system and is less expressed in various peripheral tissues such as the heart, gut, liver, and in cells such as endothelial cells and adipocytes. In comparison, CB2 is largely expressed in immune cells, tonsils, spleen, and testis. Moreover, it has been observed to be expressed to a lesser extent in other tissues and in cells like hepatic myofibroblasts (12).Recent studies have shown the dysregulation of endocannabinoid system in experimental models of bowel, liver, and heart diseases. Evidence suggests that Abstract: Cannabinoid receptor 2 (CB2) has a role in the pathology of some liver diseases. Cypermethrin (CYP) is a synthetic pyrethroid insecticide used commonly for the control of pests and vectors, and for protection of foodstuffs. In this study, the involvement of CB2 in CYP-induced liver damage in rats was investigated. CYP was applied to rats orally at a dose of 125 mg/kg bw per day for 14 days. CB2 agonist JWH-133 was administered by intraperitoneal injection at a dose of 3 mg/kg bw per day for the last 4 days of CYP toxicity. JWH-133 deteriorated the liver damage induced by CYP. JWH-133 increased serum hepatic enzyme activities (aspartate aminotransferase, alanine aminotransferase) in rats given CYP. However, it decreased lipid peroxidation. There were no differences in the levels of hepatic CB2 mRNA among the groups. CB2 receptors were expressed in a small amount in normal liver tissue. In contrast, the expression levels of CB2 in CYPtreated rats were increased in fibrocyte/fibroblast, bile duct epithelial cells, Kupffer cells, and mast cells. In conclusion, CB2 was upregulated in the liver exposed to CYP, predominantly in hepatic fibrogenic cells. JWH-133 enhanced the CYPinduced liver damage by receptor mediated and/or non...

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“…In addition, Huang et al 21 recently reported on the protective role of CROM against liver injury triggered by small intestinal ISCH/REP. Conversely, Shibamoto et al 11 found ISCH/REP-induced injury in the isolated perfused liver of genetically mast cell deficient (Ws/Ws) rats. The Shibamoto group analyzed ISCH/REP-induced injury 1 hour after REP, whereas we analyzed ISCH/REP-induced injury 2 hours after REP. 11 Most of the research studies used the 2 hours or greater time frame to investigate the role of mast cells during ISCH/REP.…”

Section: Discussionmentioning

confidence: 98%

“…Conversely, Shibamoto et al 11 found ISCH/REP-induced injury in the isolated perfused liver of genetically mast cell deficient (Ws/Ws) rats. The Shibamoto group analyzed ISCH/REP-induced injury 1 hour after REP, whereas we analyzed ISCH/REP-induced injury 2 hours after REP. 11 Most of the research studies used the 2 hours or greater time frame to investigate the role of mast cells during ISCH/REP. 12 , 22 , 23 To the best of our knowledge, no study has reported on the effect that KET has on ISCH/REP-induced liver injury; nonetheless, our results appear to be contrary to the findings from a previous study conducted by Huang et al 21 who reported a protective role of KET against liver injury triggered by small intestinal ISCH/REP.…”

Section: Discussionmentioning

confidence: 98%

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Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase

El-Shitany¹,

El-desoky²

2015

DDDT

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Hepatic ischemia/reperfusion (ISCH/REP) is a major clinical problem that is considered to be the most common cause of postoperative liver failure. Recently, mast cells have been proposed to play an important role in the pathophysiology of ISCH/REP in many organs. In contrast, the role played by mast cells during ISCH/REP-induced liver damage has remained an issue of debate. This study aimed to investigate the protective role of mast cells in order to search for an effective therapeutic agent that could protect against fatal ISCH/REP-induced liver damage. A model of warm ISCH/REP was induced in the liver of rats. Four groups of rats were used in this study: Group I: SHAM (normal saline, intravenously [iv]); Group II: ISCH/REP; Group III: sodium cromoglycate + ISCH/REP (CROM + ISCH/REP), and Group IV: ketotifen (KET) + ISCH/REP (KET + ISCH/REP). Liver damage was assessed both histopathologically and biochemically. Mast cell degranulation was assessed histochemically. Lipid peroxidation (malondialdehyde [MDA]) as well as the levels of glutathione (GSH), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), the formation of nitric oxide (NO), and the expression of inducible NO synthase (iNOS) were determined. The results of this study revealed increased mast cell degranulation in the liver during the acute phase of ISCH/REP. Moreover, CROM, but not KET, decreased the activity of alanine aminotransferase, aspartate aminotransferase, and lactic dehydrogenase and maintained normal liver tissue histology. Both CROM and KET protected against mast cell degranulation in the liver. In addition, both CROM and KET decreased IL-6 and TNF-α. However, CROM, but not KET, decreased MDA formation and increased GSH. Furthermore, KET, but not CROM, increased both NO formation and iNOS expression. In conclusion, this study clearly demonstrated mast cell degranulation in warm ISCH/REP in the liver of rats. More importantly, CROM, but not KET, ameliorated the effect of ISCH/REP-induced injury in rat liver. CROM may protect the liver through mast cell stabilization, inhibition of TNF-α, IL-6, MDA, and iNOS and increased GSH. KET may maintain ISCH/REP-induced liver injury through the NO/iNOS pathway.

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Mast Cells Are Not Involved in the Ischemia-Reperfusion Injury in Perfused Rat Liver

Cited by 7 publications

References 20 publications

Inhibition of mast cell‐secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice

Inhibition of mast cell‐secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2−/− mice

Cannabinoid receptor type 2 agonist JWH-133 deteriorates the liver toxicity induced by cypermethrin

Cromoglycate, not ketotifen, ameliorated the injured effect of warm ischemia/reperfusion in rat liver: role of mast cell degranulation, oxidative stress, proinflammatory cytokine, and inducible nitric oxide synthase

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