Molecular Medicine

, Volume 23, Issue 1, pp 134–148 | Cite as

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

  • Anju M. Philip
  • Youdong Wang
  • Antonio Mauro
  • Suzan El-Rass
  • John C. Marshall
  • Warren L. Lee
  • Arthur S. Slutsky
  • Claudia C. dos Santos
  • Xiao-Yan Wen
Research Article


Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug-development pipeline is time-consuming and expensive, and the low success rates associated with cell-based screens underline the need for whole-organism screening strategies, especially for complex pathological processes. Here, we established a lipopolysaccharide (LPS)-induced zebrafish endotoxemia model, which exhibits the major hallmarks of human sepsis, including edema and tissue/organ damage, increased vascular permeability and vascular leakage accompanied by altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and reactive oxygen species (ROS) production, reduced circulation and increased platelet aggregation. We tested the suitability of the model for phenotype-based drug screening using three primary readouts: mortality, vascular leakage and ROS production. Preliminary screening identified fasudil, a drug known to protect against vascular leakage in murine models, as a lead hit, thereby validating the utility of our model for sepsis drug screens. This zebrafish sepsis model has the potential to rapidly analyze sepsis-associated pathologies and cellular processes in the whole organism, as well as to screen and validate many compounds that can modify sepsis pathology in vivo.



We thank Koroboshka Brand-Arzamendi for the schematic diagrams/illustrations used in the paper, and for help with confocal imaging.

Supplementary material

10020_2017_2301134_MOESM1_ESM.pdf (903 kb)
Supplementary material, approximately 903 KB.


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Authors and Affiliations

  • Anju M. Philip
    • 1
    • 2
    • 3
  • Youdong Wang
    • 1
    • 2
  • Antonio Mauro
    • 1
    • 2
    • 4
    • 6
  • Suzan El-Rass
    • 1
    • 2
    • 4
    • 6
  • John C. Marshall
    • 1
    • 2
    • 5
  • Warren L. Lee
    • 1
    • 2
    • 4
  • Arthur S. Slutsky
    • 1
    • 2
    • 4
    • 5
  • Claudia C. dos Santos
    • 1
    • 2
    • 4
    • 5
  • Xiao-Yan Wen
    • 1
    • 2
    • 3
    • 4
    • 6
  1. 1.Zebrafish Centre for Advanced Drug DiscoverySt. Michael’s HospitalTorontoCanada
  2. 2.Keenan Research Centre for Biomedical ScienceLi Ka Shing Knowledge Institute of St. Michael’s HospitalTorontoCanada
  3. 3.Department of PhysiologyUniversity of TorontoTorontoCanada
  4. 4.Department of Medicine and Institute of Medical ScienceUniversity of TorontoTorontoCanada
  5. 5.Interdepartmental Division of Critical CareSt. Michael’s Hospital/University of TorontoTorontoCanada
  6. 6.Collaborative Program in Cardiovascular Sciences, Faculty of MedicineUniversity of TorontoTorontoCanada

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