Sphingosine kinase-1 mediates endotoxemia-induced hyperinflammation in aged animals

Lufrano, Maria; Jacob, Asha; Zhou, Mian; Wang, Haichao

doi:10.3892/mmr.2013.1562

Cited by 11 publications

(8 citation statements)

References 33 publications

(37 reference statements)

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“…3 Lufrano et al demonstrated that SphK1 participates in LPS-induced inflammation in aged rats. 4 Specific S1PRs play a role in the mechanism of inflammation as well. 5,6 Overall, SphK1/S1P/S1PRs signaling leads to the pathophysiology of inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

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Sphingosine kinase 1 inhibition improves lipopolysaccharide/D‐galactosamine‐induced acute liver failure by inhibiting mitogen‐activated protein kinases pathway

Tian

Yang

et al. 2016

UEG Journal

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Section: Introductionmentioning

confidence: 99%

“…Furthermore, the transcription of TNF‐α, IL‐1β and inducible nitric oxide synthase (iNOS) was attenuated as a result of the inhibition of SphK1 3 . Lufrano et al demonstrated that SphK1 participates in LPS‐induced inflammation in aged rats 4 . Specific S1PRs play a role in the mechanism of inflammation as well 5 , 6 .…”

Section: Introductionmentioning

confidence: 99%

Sphingosine kinase 1 inhibition improves lipopolysaccharide/D‐galactosamine‐induced acute liver failure by inhibiting mitogen‐activated protein kinases pathway

Tian

Yang

et al. 2016

UEG Journal

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“…[10][11][12][13] SphK1 is the major kinase that generates sphingosine-1-phosphate in blood, 14 and its protein expression and enzymatic activity are both upregulated in macrophages during endotoxemia. [15][16][17] Recently, sphingosine-1-phosphate has been suggested to be involved in NLRP3 activation. 18 However, the roles of SphK1 in polymicrobial sepsis and NLRP3 inflammasome activation have not been well addressed.…”

Section: What We Already Know About This Topicmentioning

confidence: 99%

Inhibition of Sphingosine Kinase 1 Attenuates Sepsis-induced Microvascular Leakage via Inhibiting Macrophage NLRP3 Inflammasome Activation in Mice

Zhong

Wang

et al. 2020

Anesthesiology

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Background Sepsis is the overwhelming inflammatory response to infection, in which nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome plays a crucial role. Shingosine-1-phosphate is reported to evoke NLRP3 inflammasome activation. Sphingosine kinase 1 (SphK1) is the major kinase that catalyzes bioactive lipid shingosine-1–phosphate formation and its role in sepsis remains uncertain. The authors hypothesize that SphK1 elicits NLRP3 inflammasome activation and exacerbates sepsis. Methods Peripheral blood mononuclear cells were isolated from septic patients and healthy volunteers to measure messenger RNA (mRNA) expression. In mice, sepsis was induced by cecal ligation and puncture. Bone marrow–derived macrophages were prepared from C57BL/6J wild-type, Casp1−/−, Nlrp3−/− and SphK1−/− mice. PF-543 was used as the specific inhibitor of SphK1. Mortality, peripheral perfusion, lung Evan’s blue dye index, lung wet/dry ratio, lung injury score, lung myeloperoxidase activity, NLRP3 activation, and function of endothelial adherens junction were measured. Results SphK1 mRNA expression was higher in cells from septic patients versus healthy volunteers (septic patients vs. healthy volunteers: 50.9 ± 57.0 fold change vs. 1.2 ± 0.1 fold change, P < 0.0001) and was positively correlated with IL-1β mRNA expression in these cells (r = 0.537, P = 0.012) and negatively correlated with PaO2/Fio2 ratios (r = 0.516, P = 0.017). In mice that had undergone cecal ligation and puncture, the 5-day mortality was 30% in PF-543–treated group and 80% in control group (n = 10 per group, P = 0.028). Compared with controls, PF-543–treated mice demonstrated improved peripheral perfusion and alleviated extravascular Evan’s blue dye effusion (control vs. PF-543: 25.5 ± 3.2 ng/g vs. 18.2 ± 1.4 ng/g, P < 0.001), lower lung wet/dry ratio (control vs. PF-543: 8.0 ± 0.2 vs. 7.1 ± 0.4, P < 0.0001), descending lung injury score, and weaker lung myeloperoxidase activity. Inhibition of SphK1 suppressed caspase-1 maturation and interleukin-1β release through repressing NLRP3 inflammasome activation, and subsequently stabilized vascular endothelial cadherin through suppressing interleukin-1β–evoked Src-mediated phosphorylation of vascular endothelial cadherin. Conclusions SphK1 plays a crucial role in NLRP3 inflammasome activation and contributes to lung injury and mortality in mice polymicrobial sepsis. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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“…Existing evidence has emerged to suggest the essential roles of SphKl and S1PR1 in inflammatory response [ 8 ]. SphKl was found to be involved in inflammatory responses in elderly rats [ 9 ]. The expression of S1PR1 in human gingival epithelial cells was upregulated after endotoxin stimulation, along with augmented contents of inflammatory factors [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Blocking SphK1/S1P/S1PR1 Signaling Pathway Alleviates Lung Injury Caused by Sepsis in Acute Ethanol Intoxication Mice

Chen

Song

2021

Inflammation

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Acute ethanol intoxication increases the risk of sepsis and aggravates the symptoms of sepsis and lung injury. Therefore, this study aimed to explore whether sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P)/S1P receptor 1 (S1PR1) signaling pathway functions in lung injury caused by acute ethanol intoxication-enhanced sepsis, as well as its underlying mechanism. The acute ethanol intoxication model was simulated by intraperitoneally administering mice with 32% ethanol solution, and cecal ligation and puncture (CLP) was used to construct the sepsis model. The lung tissue damage was observed by hematoxylin-eosin (H&E) staining, and the wet-to-dry (W/D) ratio was used to evaluate the degree of pulmonary edema. Inflammatory cell counting and protein concentration in bronchoalveolar lavage fluid (BALF) were, respectively, detected by hemocytometer and bicinchoninic acid (BCA) method. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-18 in BALF were detected by their commercial enzyme-linked immunosorbent assay (ELISA) kits. The myeloperoxidase (MPO) activity and expression of apoptosis-related proteins and SphK1/S1P/S1PR1 pathway-related proteins were, respectively, analyzed by MPO ELISA kit and Western blot analysis. The cell apoptosis in lung tissues was observed by TUNEL assay. Acute ethanol intoxication (EtOH) decreased the survival rate of mice and exacerbated the lung injury caused by sepsis through increasing pulmonary vascular permeability, neutrophil infiltration, release of inflammatory factors, and cell apoptosis. In addition, EtOH could activate the SphK1/S1P/S1PR1 pathway in CLP mice. However, PF-543, as a specific inhibitor of SphK1, could partially reverse the deleterious effects on lung injury of CLP mice. PF-543 alleviated lung injury caused by sepsis in acute ethanol intoxication rats by suppressing the SphK1/S1P/S1PR1 signaling pathway.

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Sphingosine kinase-1 mediates endotoxemia-induced hyperinflammation in aged animals

Cited by 11 publications

References 33 publications

Sphingosine kinase 1 inhibition improves lipopolysaccharide/D‐galactosamine‐induced acute liver failure by inhibiting mitogen‐activated protein kinases pathway

Sphingosine kinase 1 inhibition improves lipopolysaccharide/D‐galactosamine‐induced acute liver failure by inhibiting mitogen‐activated protein kinases pathway

Inhibition of Sphingosine Kinase 1 Attenuates Sepsis-induced Microvascular Leakage via Inhibiting Macrophage NLRP3 Inflammasome Activation in Mice

Blocking SphK1/S1P/S1PR1 Signaling Pathway Alleviates Lung Injury Caused by Sepsis in Acute Ethanol Intoxication Mice

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