ZFIN ID: ZDB-PUB-161126-3
A whole animal chemical screen approach to identify modifiers of intestinal neutrophilic inflammation
Oehlers, S.H., Flores, M.V., Hall, C.J., Wang, L., Ko, D.C., Crosier, K.E., Crosier, P.S.
Date: 2017
Source: The FEBS journal   284(3): 402-413 (Journal)
Registered Authors: Crosier, Kathy, Crosier, Phil, Flores, Maria, Hall, Chris, Oehlers, Stefan
Keywords: Colitis, IBD, Inflammation, chemical screen, neuro-immune
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Anti-Inflammatory Agents/pharmacology*
  • Colitis, Ulcerative/chemically induced
  • Colitis, Ulcerative/drug therapy*
  • Colitis, Ulcerative/immunology
  • Colitis, Ulcerative/pathology
  • Crohn Disease/chemically induced
  • Crohn Disease/drug therapy*
  • Crohn Disease/immunology
  • Crohn Disease/pathology
  • Dextran Sulfate
  • Disease Models, Animal
  • Dopamine Agonists/pharmacology
  • Dysbiosis/chemically induced
  • Dysbiosis/drug therapy*
  • Dysbiosis/immunology
  • Dysbiosis/pathology
  • Embryo, Nonmammalian
  • Gene Expression
  • High-Throughput Screening Assays*
  • Humans
  • Immunologic Factors/pharmacology*
  • Intestines/drug effects
  • Intestines/immunology
  • Intestines/pathology
  • Neutrophils/drug effects
  • Neutrophils/immunology
  • Neutrophils/pathology
  • Receptors, Cholecystokinin/agonists
  • Receptors, Cholecystokinin/genetics
  • Receptors, Cholecystokinin/immunology
  • Receptors, Dopamine/genetics
  • Receptors, Dopamine/immunology
  • Small Molecule Libraries/pharmacology
  • Trinitrobenzenesulfonic Acid
  • Zebrafish
PubMed: 27885812 Full text @ FEBS J.
By performing two high-content small molecule screens on DSS- and TNBS-induced zebrafish enterocolitis models of inflammatory bowel disease, we have identified novel anti-inflammatory drugs from the John Hopkins Clinical Compound Library that suppress neutrophilic inflammation. Live imaging of neutrophil distribution was used to assess the level of acute inflammation and concurrently screen for off-target drug effects. Supporting the validity of our screening strategy, most of the anti-inflammatory drug hits were known antibiotics or anti-inflammatory agents. Novel hits included cholecystokinin (CCK) and dopamine receptor agonists. Using a pharmacological approach, we show that while CCK and dopamine receptor agonists alleviate enterocolitis-associated inflammation, receptor antagonists exacerbate inflammation in zebrafish. This work highlights the utility of small molecule screening in zebrafish enterocolitis models as a tool to identify novel bioactive molecules capable of modulating acute inflammation.