title: A whole animal chemical screen approach to identify modifiers of intestinal neutrophilic inflammation.
abstract: By performing two high-content small molecule screens on dextran sodium sulfate- and trinitrobenzene sulfonic acid-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.
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, New Zealand.|Tuberculosis Research Program, Centenary Institute, Camperdown, NSW, Australia.|Sydney Medical School, The University of Sydney, Newtown, NSW, Australia.
authors.forename: Stefan H
authors.identifier: 0000-0003-0260-672X
authors.initials: SH
authors.lastname: Oehlers
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, New Zealand.
authors.forename: Maria Vega
authors.initials: MV
authors.lastname: Flores
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, New Zealand.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hall
authors.affiliation: Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC, USA.
authors.forename: Liuyang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC, USA.|Department of Medicine, School of Medicine, Duke University, Durham, NC, USA.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Ko
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, New Zealand.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Crosier
authors.affiliation: Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, New Zealand.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Crosier
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003424:Crohn Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D064806:Dysbiosis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004625:Embryo, Nonmammalian; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D011949:Receptors, Cholecystokinin / Q000819:agonists / Q000235:genetics / Q000276:immunology; D011954:Receptors, Dopamine / Q000235:genetics / Q000276:immunology; D054852:Small Molecule Libraries / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid; D015027:Zebrafish
chemical_list: D000893:Anti-Inflammatory Agents; D018491:Dopamine Agonists; D007155:Immunologic Factors; D011949:Receptors, Cholecystokinin; D011954:Receptors, Dopamine; D054852:Small Molecule Libraries; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate
keywords: chemical screen; colitis; inflammation; inflammatory bowel disease; neuro-immune