MK-571 Attenuates Kidney Ischemia and Reperfusion–Induced Airway Hypersensitivity in Rats

Wu, Nan; Tong, Song; Yang, Y.-C.; Wang, J.-C.; Wang, J.-J.

doi:10.1016/j.transproceed.2013.12.041

Cited by 2 publications

(6 citation statements)

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“…MK571 possesses a pharmacological profile as an antagonist of the leukotriene D4 receptor. 28 Therefore, we performed 2 additional experiments to determine whether leukotriene antagonism reduces anoxia-reoxygenation–induced cell death or whether inhibition of MRP transporter activity reduced cell death. First, during cardiac IR injury, leukotrienes, produced by infiltrating neutrophils, induce surrounding inflammatory cells to accelerate inflammation.…”

Section: Resultsmentioning

confidence: 99%

“…54,55 However, MK571 also acts as an antagonist of the leukotriene D4 receptor. 28 Therefore, we investigated whether IR injury was reduced by the leukotriene antagonism of MK571 or by the inhibition of MRP1 transporter activity. We measured MPO activity as an indicator of the number of neutrophils migrating during cardiac IR.…”

Section: Glutathione Release During Ir Injury Was Mediated By Mrp1mentioning

confidence: 99%

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MRP1-Dependent Extracellular Release of Glutathione Induces Cardiomyocyte Ferroptosis After Ischemia-Reperfusion

Ichihara,

Katsumata,

Sugiura

et al. 2023

Circulation Research

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Background: The membrane components of cardiomyocytes are rich in polyunsaturated fatty acids, which are easily oxidized. Thus, an efficient glutathione-based lipid redox system is essential for maintaining cellular functions. However, the relationship between disruption of the redox system during ischemia-reperfusion (IR), oxidized lipid production, and consequent cell death (ferroptosis) remains unclear. We investigated the mechanisms underlying the disruption of the glutathione-mediated reduction system related to ferroptosis during IR and developed intervention strategies to suppress ferroptosis. Methods: In vivo fluctuations of both intra- and extracellular metabolite levels during IR were explored via microdialysis and tissue metabolome analysis. Oxidized phosphatidylcholines were assessed using liquid chromatography high-resolution mass spectrometry. The areas at risk following IR were assessed using triphenyl-tetrazolium chloride/Evans blue stain. Results: Metabolomic analysis combined with microdialysis revealed a significant release of glutathione from the ischemic region into extracellular spaces during ischemia and after reperfusion. The release of glutathione into extracellular spaces and a concomitant decrease in intracellular glutathione concentrations were also observed during anoxia-reperfusion in an in vitro cardiomyocyte model. This extracellular glutathione release was prevented by chemical inhibition or genetic suppression of glutathione transporters, mainly MRP1 (multidrug resistance protein 1). Treatment with MRP1 inhibitor reduced the intracellular reactive oxygen species levels and lipid peroxidation, thereby inhibiting cell death. Subsequent in vivo evaluation of endogenously oxidized phospholipids following IR demonstrated the involvement of ferroptosis, as levels of multiple oxidized phosphatidylcholines were significantly elevated in the ischemic region 12 hours after reperfusion. Inhibition of the MRP1 transporter also alleviated intracellular glutathione depletion in vivo and significantly reduced the generation of oxidized phosphatidylcholines. Administration of MRP1 inhibitors significantly attenuated infarct size after IR injury. Conclusions: Glutathione was released continuously during IR, primarily in an MRP1-dependent manner, and induced ferroptosis. Suppression of glutathione release attenuated ferroptosis and reduced myocardial infarct size following IR.

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Section: Resultsmentioning

confidence: 99%

Section: Glutathione Release During Ir Injury Was Mediated By Mrp1mentioning

confidence: 99%

MRP1-Dependent Extracellular Release of Glutathione Induces Cardiomyocyte Ferroptosis After Ischemia-Reperfusion

Ichihara,

Katsumata,

Sugiura

et al. 2023

Circulation Research

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“…Recently, the role played by CysLTs in the visceral I/R injury were noted [3,7,10,12]. Takamatsu et al [3] showed that serum levels of CysLTs, generated in the liver during hepatic reperfusion, increased by 4-fold in 12 hours and 5-fold in 24 hours of I/R injury and promoted edema and neutrophil infiltration in the liver and lung tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, LTB4 facilitates inflammatory cell infiltration, and LTD4 regulates increases in pulmonary arterial pressure and vascular permeability [6]. MK-571 has a chemical formula of C 26 H 26 C l N 2 NaO 3 S 2 $ xH 2 O and a molecular weight of 571.37 Da [7]. MK-571, also known as 5-(3-(2-(7-chloroquinolin-2-yl)ethenyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoic acid, is a potent LTD4 receptor antagonist and an effective inhibitor of multidrug resistance-associated protein (MRP)1 and MRP2 [8].…”

mentioning

confidence: 99%

“…Previously, Failla et al [11] showed that MK-571 can reduce bleomycin-induced interleukin (IL)-1 level and collagen deposition in the lungs. More recently, Wu and Wang [7] demonstrated that MK-571 attenuates airway hypersensitivity induced by renal I/R injury. In the present study, we aimed to investigate the protective efficacy of treatment with MK-571 against hepatic warm I/R injuryeinduced remote lung injury, assessed by means of the pulmonary capillary filtration coefficient (K fc ) and lung-water content by means of the wet-to-dry lung weight ratio (W/D) and the lung weightetoebody weight ratio and trans-capillary protein permeability through the protein concentration in the bronchoalveolar lavage fluid (PCBAL).…”

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confidence: 99%

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