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Diseases of failed inflammation resolution are common and largely incurable. Therapeutic induction of inflammation resolution is an attractive strategy to bring about healing without increasing susceptibility to infection. However, therapeutic targeting of inflammation resolution has been hampered by a lack of understanding of the underlying molecular controls. To address this drug development challenge, we developed an in vivo screen for proresolution therapeutics in a transgenic zebrafish model. Inflammation induced by sterile tissue injury was assessed for accelerated resolution in the presence of a library of known compounds. Of the molecules with proresolution activity, tanshinone IIA, derived from a Chinese medicinal herb, potently induced inflammation resolution in vivo both by induction of neutrophil apoptosis and by promoting reverse migration of neutrophils. Tanshinone IIA blocked proinflammatory signals in vivo, and its effects are conserved in human neutrophils, supporting a potential role in treating human inflammation and providing compelling evidence of the translational potential of this screening strategy.

Original publication

DOI

10.1126/scitranslmed.3007672

Type

Journal article

Journal

Science translational medicine

Publication Date

02/2014

Volume

6

Addresses

Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield S10 2TN, UK.

Keywords

Neutrophils, Cells, Cultured, Animals, Animals, Genetically Modified, Zebrafish, Humans, Disease Models, Animal, Inflammation, Diterpenes, Abietane, Green Fluorescent Proteins, Anti-Inflammatory Agents, Drug Evaluation, Preclinical, Signal Transduction, Apoptosis, Cell Movement, Neutrophil Infiltration, Larva, Dose-Response Relationship, Drug, Time Factors, High-Throughput Screening Assays, Translational Medical Research