Systemic neutrophil intrinsic 5‐lipoxygenase activity and CD 18 receptor expression linked to reperfusion injury

Dolan, Robert W.; Hartshorn, Kevan L.; Andry, Chris; Mcavoy, Daniel

doi:10.1097/00005537-199809000-00025

Cited by 9 publications

(8 citation statements)

References 18 publications

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“…In mouse renal I/R model, Patel et al (28) demonstrated that degree of renal dysfunction and tissue injury was preserved along with reduced intercellular adhesion molecule-1 expression and neutrophil infiltration in kidneys in 5-LOX knockout mice and by treatment with 5-LOX inhibitor zileuton. These findings were in accordance with those of a previous study demonstrating that zileuton reduced CD18 adhesion receptor expression on systemic neutrophils and attenuated I/R injury in guinea pig skin flaps (29). In rat brain damage induced by cerebral ischemia, zileuton was found to be effective in reducing brain damage via decreasing MDA content, and inhibition of NF-kB and inducible nitric oxide synthase (iNOS) expression (30).…”

Section: Discussionsupporting

confidence: 93%

Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction

et al. 2016

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Objective:The goal of the present study was to investigate the effects of 5-lipoxygenase (5-LOX) inhibition, alone and with cyclooxygenase (COX) inhibitors, on inflammatory parameters and apoptosis in ischemia/reperfusion (I/R)-induced myocardial damage in rats. For this purpose, zileuton, a selective and potent inhibitor of 5-LOX, resulting in suppression leukotriene production, was used.Methods:Male Wistar rats (200-250 g; n=12 per group) were used in the study. I/R was performed by occluding the left coronary artery for 30 minutes and 2 hours of reperfusion of the heart. Experimental groups were I/R group, sham I/R group, zileuton (5 mg/kg orally, twice daily)+I/R group, zileuton+indomethacin (5 mg/kg intraperitoneally)+I/R group, zileuton+ketorolac (10 mg/kg subcutaneously)+I/R group, and zileuton+nimesulide (5 mg/kg subcutaneously)+I/R group. Following I/R, blood samples were collected to measure tumor necrosis factor alpha (TNF-α), and left ventricles were excised for evaluation of microscopic damage; malondialdehyde (MDA), glutathione, nuclear factor (NF)-κB assays; and evaluation of apoptosis.Results:Left ventricle MDA in I/R group was higher compared to sham group; however, it did not show significant change with zileuton. Although tissue injury in I/R group was less severe in all treatment groups, it was not statistically significant. NF-κB H-score and apoptotic index, which were higher in I/R group compared to sham I/R, were decreased with application of zileuton (H-score: p<0.01; apoptotic index: p<0.001). Zileuton had no significant effect on increased serum TNF-α levels in I/R group.Conclusion:5-LOX inhibition in rat myocardial infarction model attenuated increased left ventricle NF-κB expression and apoptosis and these actions were not modulated by COX inhibitors. (Anatol J Cardiol 2017; 17: 269-75)

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Section: Discussionsupporting

confidence: 93%

Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction

et al. 2016

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“…It has been shown that myocardial I/R promotes the release and metabolism of leukotrienes (LTs), which are metabolites of arachidonic acid formed from the 5-LOX pathway and exert potent vasoactive and proinflammatory effects (12). LTs also play roles in I/R of skin, brain, and kidney (8,11,34), and 5-LOX inhibitors have been suggested to be useful in the treatment of conditions associated with I/R of the kidney (34). However, the effects of 5-LOX inhibitors on mycardial I/R are rather controversial.…”

Section: Discussionmentioning

confidence: 99%

N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1

Zhong¹,

Wang²

2008

American Journal of Physiology-Heart and Circulatory Physiology

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N-oleoyldopamine (OLDA), a bioactive lipid originally found in the mammalian brain, is an endovanilloid that selectively activates the transient receptor potential vanilloid type 1 (TRPV1) channel. This study tests the hypothesis that OLDA protects the heart against ischemia and reperfusion (I/R) injury via activation of the TRPV1 in wild-type (WT) but not in gene-targeted TRPV1-null mutant (TRPV1(-/-)) mice. Hearts of WT or TRPV1(-/-) mice were Langendorffly perfused with OLDA (2 x 10(-9) M) in the presence or absence of CGRP8-37 (1 x 10(-6) M), a selective calcitonin gene-related peptide (CGRP) receptor antagonist; RP-67580 (1 x 10(-6) M), a selective neurokinin-1 receptor antagonist; chelerythrine (5 x 10(-6) M), a selective protein kinase C (PKC) antagonist; or tetrabutylammonium (TBA, 5 x 10(-4) M), a nonselective K(+) channel antagonist, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), coronary flow (CF), and left ventricular peak positive dP/dt (+dP/dt) were evaluated after I/R. OLDA improved recovery of cardiac function after I/R in WT but not TRPV1(-/-) hearts by increasing LVDP, CF, and +dP/dt and by decreasing LVEDP. CGRP8-37, RP-67580, chelerythrine, or TBA abolished the protective effect of OLDA in WT hearts. Radioimmunoassay showed that the release of substance P (SP) and CGRP after OLDA treatment was higher in WT than in TRPV1(-/-) hearts, which was blocked by chelerythrine or TBA. Thus OLDA exerts a cardiac protective effect during I/R injury in WT hearts via CGRP and SP release, which is abolished by PKC or K(+) channel antagonists. The protective effect of OLDA is void in TRPV1(-/-) hearts, supporting the notion that TRPV1 mediates OLDA-induced protection against cardiac I/R injury.

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“…LTs are involved in the genesis of inflammation and edema, because of their effects on vascular permeability, plasma extravasation, and diapedesis of white blood cells [6,7], and they may also play an important role in adaptive immune responses [8]. There is now good evidence that LTs play a pivotal role in the pathophysiology of asthma [9,10] and psoriasis [11,12], as well as in conditions associated with ischemia-reperfusion (I/R) of skin [13,14], brain [15], and kidney [13,16,17]. LTs also play a physiological role in the host defense against microbial infections [18].…”

Section: Introductionmentioning

confidence: 99%

Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton

Collin

Rossi

Cuzzocrea

et al. 2004

Journal of Leukocyte Biology

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The role of 5-lipoxygenase (5-LOX) in the pathophysiology of the organ injury/dysfunction caused by endotoxin is not known. Here, we investigate the effects of treatment with 5-LOX inhibitor zileuton in rats and targeted disruption of the 5-LOX gene in mice (5-LOX(-/-)) on multiple organ injury/dysfunction caused by severe endotoxemia. We also investigate the expression of beta2-integrins CD11a/CD18 and CD11b/CD18 on rat leukocytes by flow cytometry. Zileuton [3 mg/kg intravenously (i.v.)] or vehicle (10% dimethyl sulfoxide) was administered to rats 15 min prior to lipopolysaccharide (LPS; Escherichia coli, 6 mg/kg i.v.) or vehicle (saline). 5-LOX(-/-) mice and wild-type littermate controls were treated with LPS (E. coli, 20 mg/kg intraperitoneally) or vehicle (saline). Endotoxemia for 6 h in rats or 16 h in mice resulted in liver injury/dysfunction (increase in the serum levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin), renal dysfunction (creatinine), and pancreatic injury (lipase, amylase). Absence of functional 5-LOX (zileuton treatment or targeted disruption of the 5-LOX gene) reduced the multiple organ injury/dysfunction caused by endotoxemia. Polymorphonuclear leukocyte infiltration (myeloperoxidase activity) in the lung and ileum as well as pulmonary injury (histology) were markedly reduced in 5-LOX(-/-) mice. Zileuton also reduced the LPS-induced expression of CD11b/CD18 on rat leukocytes. We propose that endogenous 5-LOX metabolites enhance the degree of multiple organ injury/dysfunction caused by severe endotoxemia by promoting the expression of the adhesion molecule CD11b/CD18 and that inhibitors of 5-LOX may be useful in the therapy of the organ injury/dysfunction associated with endotoxic shock.

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Systemic neutrophil intrinsic 5‐lipoxygenase activity and CD 18 receptor expression linked to reperfusion injury

Abstract: Zileuton, a 5-LO inhibitor, reduces adhesion receptor expression on systemic neutrophils and attenuates i/r injury. Systemic neutrophil intrinsic 5-LO activity and CD18 receptor expression are linked to reperfusion injury and may be fundamental events in its pathogenesis.

Cited by 9 publications

References 18 publications

Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction

Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction

N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1

Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton

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