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Preclinical evidence of sphingosine kinase 1 inhibition in alleviation of intestinal epithelial injury in polymicrobial sepsis

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Abstract

Background

Intestinal epithelial injury in septic patients predicts subsequent development of multiple organ failure, but its regulation by host factors remains unclear. Sphingosine kinase 1 is an enzyme-regulating inflammatory response.

Methods

Cecal ligation and puncture was used to induce sepsis in C57BL/6 mice with and without N,N-dimethylsphingosine, a SphK1 inhibitor. Symptom severity was monitored by murine sepsis severity score. The intestinal barrier function was determined using 4KDa fluorescein-dextran. Bacterial load in the bloodstream was determined by 16S rRNA gene amplification.

Results and conclusions

Our preliminary experimental data showed that expression of sphingosine kinase 1 in ileum was increased by sixfold in septic mice. Pharmacological blockade of sphingosine kinase 1 alleviated septic symptoms. The intestinal permeability and bacterial load in the bloodstream were also reduced in these animals. We hypothesized that inhibition of sphingosine kinase 1 may reduce pro-inflammatory cytokine production, and alleviate intestinal epithelial injury during sepsis. Further mechanistic studies and clinical specimen analyses are warranted.

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Acknowledgements

Part of this study was presented in International Sepsis Forum, Bangkok, Thailand, October 2018. The authors would like to thank Health and Medical Research Fund, Food and Health Bureau, The Government of Hong Kong Special Administrative Region, China (05160746) for supporting this study.

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Authors and Affiliations

  1. Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China

    Felix Nnaemeka Ugwu

  2. Department of Microbiology, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China

    Jeffery Ho

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  1. Felix Nnaemeka Ugwu
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  2. Jeffery Ho
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Correspondence to Jeffery Ho.

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Ugwu, F.N., Ho, J. Preclinical evidence of sphingosine kinase 1 inhibition in alleviation of intestinal epithelial injury in polymicrobial sepsis. Inflamm. Res. 68, 723–726 (2019). https://doi.org/10.1007/s00011-019-01255-7

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  • DOI: https://doi.org/10.1007/s00011-019-01255-7

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