Understanding the pathophysiology of acute critical illness: translational lessons from zebrafish models.

Abstract

The models used to investigate the pathophysiological mechanisms of acute critical illness are not limited to mammalian species. The zebrafish (Danio rerio) is a popular model organism for studying diseases due to its transparency and rapid development. The genes and signaling pathways involved in acute critical illness appear highly conserved among zebrafish and humans. Forward genetics such as random mutagenesis by a chemical mutagen or reverse genetics methods represented by CRISPR/Cas9 allowed researchers to reveal multiple novel aspects of pathological processes in areas including infection, immunity, and regeneration. As a model of sepsis, transgenic zebrafish allowed the visualization of lipopolysaccharide (LPS)-induced vascular leakage in vivo and the demonstration of changes in the expression of cellular junction proteins. Other transgenic zebrafish visualizing the extravascular migration of neutrophils and macrophages have demonstrated a decrease in neutrophil numbers and an increased expression of an inflammatory gene, which replicates a phenomenon observed in humans in clinically encountered sepsis. The regenerative potential and the visibility of zebrafish organs also enabled clarification of important mechanisms in wound healing, angiogenesis, and neurogenesis. After spinal cord injury (SCI), a marker gene expressed in glial bridging was discovered. Furthermore, localized epithelial-to-mesenchymal transition (EMT) and molecular mechanisms leading to spinal cord repair were revealed. These translational studies using zebrafish show the potential of the model system for the treatment of acute critical illnesses such as sepsis, organ failure, and trauma.