title: A Zebrafish Drug-Repurposing Screen Reveals sGC-Dependent and sGC-Independent Pro-Inflammatory Activities of Nitric Oxide.
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.
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Wittmann
authors.affiliation: Institute for Applied Computer Science, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Reischl
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
authors.forename: Asmi H
authors.initials: AH
authors.lastname: Shah
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Kronfuss
authors.affiliation: Institute for Applied Computer Science, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Mikut
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
authors.forename: Urban
authors.initials: U
authors.lastname: Liebel
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Grabher
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D019327:Copper Sulfate / Q000633:toxicity; D058492:Drug Repositioning / Q000379:methods*; D016166:Free Radical Scavengers / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006162:Guanylate Cyclase / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics; D018836:Inflammation Mediators / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects; D007962:Leukocytes / Q000276:immunology; D060172:Morpholinos / Q000235:genetics; D009092:Mucous Membrane / Q000187:drug effects / Q000293:injuries; D009569:Nitric Oxide / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D017933:Peripheral Nervous System / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D015027:Zebrafish
chemical_list: D000893:Anti-Inflammatory Agents; D016166:Free Radical Scavengers; D018836:Inflammation Mediators; D060172:Morpholinos; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D019327:Copper Sulfate