Leukotriene D4 activates a chloride conductance in hepatocytes from lipopolysaccharide-treated rats.

Meng, Xianmin; Carruth, Michael W.; Weinman, Steven A.

doi:10.1172/jci119486

Cited by 25 publications

(21 citation statements)

References 48 publications

(47 reference statements)

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“…We have previously shown that under specific cell culture conditions, inclusion of (leukotriene D 4 ) LTD 4 inside the patch clamp pipet activated chloride channels in hepatocytes. 13 This was observed in hepatocytes isolated from lipopolysaccharide (LPS)-treated rats and the effect could be reproduced by in vitro treatment of hepatocytes with conditioned medium from LPS-treated RAW 264.7 cells. Figure 1A shows the current-voltage (I-V) relationship of these LTD 4 -induced currents.…”

Section: Resultsmentioning

confidence: 98%

“…18 Conditioned medium, containing a cytokine mixture, was derived from the supernatant of RAW 264.7 cells by the method originally described by Cerami et al 19 as previously described. 13 In some experiments this medium was added to the hepatocyte cultures at a dilution of 1:5. TR-rats were donated by Dr. J.L.…”

Section: Methodsmentioning

confidence: 99%

“…Whole-cell patch clamp was performed by the methods previously described. 13,18 Pipet solution contained (in mmol/L): CsCl 120, MgSO4 3, CaCl2 1, ethylene glycol-bis(␤-aminoethyl ether)-N,N,NЈ,NЈ-tertraacetic acid 11, Na2ATP 3, HEPES 10, Glucose 10; pH 7.2 using CsOH; osmolality 290 mosmol/kg adjusted by adding sucrose. These solutions result in a reversal potential near zero for chloride currents.…”

Section: Methodsmentioning

confidence: 99%

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Mrp2 modulates the activity of chloride channels in isolated hepatocytes

Weinman

2002

Hepatology

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Adenosine triphosphate binding cassette family transport proteins are important organic ion transporters in hepatocytes but these molecules may also exhibit other functions. In the present study we have measured the effects of substrates of the canalicular organic ion transporter multidrug resistance associated protein 2 (Mrp2) on chloride channel activation and cell volume regulation. We found that substrates such as leukotriene D 4 , 17-␤-estradiol glucuronide, and the leukotriene inhibitor MK-571 accelerated the activation of chloride channels by cell swelling and activated chloride channels in cytokine-pretreated hepatocytes. Two conjugated estrogens that are not Mrp2 substrates did not produce this effect. Hepatocytes derived from a strain of transport-deficient rats (TR ؊ ), which lack Mrp2 expression, showed none of these substrate effects. Coincident with their ability to activate channels, the Mrp2 substrates increased the rate of volume regulatory decrease by approximately 50% (P < .01), confirming that enhanced channel activation under this condition stimulated volume regulation. In TR-hepatocytes the Mrp2 substrate had no effect on volume regulation.

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Section: Resultsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Mrp2 modulates the activity of chloride channels in isolated hepatocytes

Weinman

2002

Hepatology

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“…5 One postulated mechanism is the activation of chloride conductance in hepatocytes. 3 An interesting new aspect of Cys-LT-induced liver injury in cholestasis is described here. After BDL, Cys-LTs can no longer be excreted via the bile.…”

Section: Discussionmentioning

confidence: 97%

“…[1][2][3] Accordingly, the inhibition of leukotriene synthesis or the blockade of cysteinyl-leukotriene (Cys-LT) receptor 1 has been shown to protect against liver injury. 4,5 However, elevated leukotriene synthesis is not detected in all forms of acute liver injury.…”

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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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Expression and regulation of leukotriene-synthesis enzymes in rat liver cells

et al. 1998

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The liver plays a major role in metabolism and elimination of leukotrienes (LT). It produces cysteinyl leukotrienes (cLT), and cLT have been implicated in hepatocellular toxicity in several models of lipopolysaccharide (LPS)-associated liver injury. However, the liver cell types responsible for cLT production are poorly defined, and the expression of the LT-synthesis enzymes, 5-lipoxygenase Leukotrienes (LT), a class of proinflammatory eicosanoids, 1,2 are metabolized by the liver, 2-4 secreted into bile by an adenosine triphosphate-dependent organic anion transporter in the canalicular membrane, 5 and are associated with several models of inflammatory liver injury. 3,4 The cysteinyl leukotrienes (cLT), LTC 4 , LTE 4 , and LTD 4 , produce smooth muscle contraction and vascular permeability changes underlying diseases such as bronchial asthma, allergic rhinitis, and rheumatoid arthritis.

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Leukotriene D4 activates a chloride conductance in hepatocytes from lipopolysaccharide-treated rats.

Cited by 25 publications

References 48 publications

Mrp2 modulates the activity of chloride channels in isolated hepatocytes

Mrp2 modulates the activity of chloride channels in isolated hepatocytes

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

Expression and regulation of leukotriene-synthesis enzymes in rat liver cells

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