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

Authors
Anju M Philip, Youdong Wang, Antonio Mauro, Suzan El-Rass, John C Marshall, Warren L Lee, Arthur S Slutsky, Claudia C dos Santos, and Xiao-Yan Wen
Abstract
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.
Volume
2017
Page Range
134-148
DOI
10.2119/molmed.2016.00188
Date Published
June 7, 2017
Article PDF
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Supplemental Data
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Keywords
Philip, Wang, Mauro, El-Rass, Marshall, Lee, Slutsky, dos Santos, Wen, sepsis, inflammation, immune response, zebrafish, fasudil, vascular leakage, drug development, somitogenesis
Article Type
Research Article