ZFIN ID: ZDB-PUB-151008-3
A Zebrafish Drug-Repurposing Screen Reveals sGC-Dependent and sGC-Independent Pro-Inflammatory Activities of Nitric Oxide
Wittmann, C., Reischl, M., Shah, A.H., Kronfuss, E., Mikut, R., Liebel, U., Grabher, C.
Date: 2015
Source: PLoS One   10: e0137286 (Journal)
Registered Authors: Grabher, Clemens, Liebel, Urban, Mikut, Ralf, Shah, Asmi, Wittmann, Christine
Keywords: Inflammation, Nitric oxide, Zebrafish, Larvae, S-nitrosylation, White blood cells, Library screening, Peripheral nervous system
MeSH Terms:
  • Animals
  • Anti-Inflammatory Agents/pharmacology
  • Cells, Cultured
  • Copper Sulfate/toxicity
  • Drug Repositioning/methods*
  • Free Radical Scavengers/pharmacology
  • Gene Knockdown Techniques
  • Guanylate Cyclase/metabolism*
  • Inflammation/drug therapy*
  • Inflammation/genetics
  • Inflammation Mediators/pharmacology*
  • Larva/drug effects
  • Leukocytes/immunology
  • Morpholinos/genetics
  • Mucous Membrane/drug effects
  • Mucous Membrane/injuries
  • Nitric Oxide/pharmacology*
  • Nitric Oxide Synthase Type I/genetics
  • Nitric Oxide Synthase Type II/genetics
  • Peripheral Nervous System/drug effects
  • Receptors, Cytoplasmic and Nuclear/metabolism*
  • Soluble Guanylyl Cyclase
  • Zebrafish
PubMed: 26444552 Full text @ PLoS One
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ABSTRACT
Tissue injury and infection trigger innate immune responses. However, dysregulation may result in chronic inflammation and is commonly treated with corticosteroids and non-steroidal anti-inflammatory drugs. Unfortunately, long-term administration of both therapeutic classes can cause unwanted side effects. To identify alternative immune-modulatory compounds we have previously established a novel screening method using zebrafish larvae. Using this method we here present results of an in vivo high-content drug-repurposing screen, identifying 63 potent anti-inflammatory drugs that are in clinical use for other indications. Our approach reveals a novel pro-inflammatory role of nitric oxide. Nitric oxide affects leukocyte recruitment upon peripheral sensory nervous system or epithelial injury in zebrafish larvae both via soluble guanylate cyclase and in a soluble guanylate cyclase -independent manner through protein S-nitrosylation. Together, we show that our screening method can help to identify novel immune-modulatory activities and provide new mechanistic insights into the regulation of inflammatory processes.
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