Development of a zebrafish sepsis model for high-throughput drug discovery
- Philip, A.M., Wang, Y., Mauro, A., El-Rass, S., Marshall, J.C., Lee, W.L., Slutsky, A.S., dos Santos, C.C., Wen, X.Y.
- Molecular medicine (Cambridge, Mass.) 23: 134-148 (Journal)
- Registered Authors
- Wen, Xiao-Yan
- endothelial dysfunction, endotoxin, lipopolysaccharide, sepsis, vascular leakage, zebrafish
- MeSH Terms
- Disease Models, Animal*
- Drug Discovery*
- Embryo, Nonmammalian
- High-Throughput Screening Assays*
- Macrophages/drug effects
- Neutrophils/drug effects
- Reactive Oxygen Species/immunology
- Sepsis*/drug therapy
- 28598490 Full text @ Mol. Med.
Philip, A.M., Wang, Y., Mauro, A., El-Rass, S., Marshall, J.C., Lee, W.L., Slutsky, A.S., dos Santos, C.C., Wen, X.Y. (2017) Development of a zebrafish sepsis model for high-throughput drug discovery. Molecular medicine (Cambridge, Mass.). 23:134-148.
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 an 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 an altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and 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 large numbers of compounds that can modify sepsis pathology in vivo.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes