A whole animal chemical screen approach to identify modifiers of intestinal neutrophilic inflammation

详细信息    查看全文

• 作者：Stefan H. Oehlers ; Maria Vega Flores ; Christopher J. Hall ; Liuyang Wang ; Dennis C. Ko ; Kathryn E. Crosier ; Philip S. Crosier
• 刊名：FEBS Journal
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：284
• 期：3
• 页码：402-413
• 全文大小：1021.6KB
• ISSN：1742-4658

文摘

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.