Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse.
Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse.
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DOI：
10.1016/j.ydbio.2015.09.023
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发表时间：
2016-01-15
影响因子：
2.7
通讯作者：
Heuckeroth RO
中科院分区：
文献类型：
--
作者：
Schill EM;Lake JI;Tusheva OA;Nagy N;Bery SK;Foster L;Avetisyan M;Johnson SL;Stenson WF;Goldstein AM;Heuckeroth RO
先天性巨结肠是一种潜在的致命性先天缺陷，其特征是远端肠神经系统（ENS）缺失。虽然HSCR有明确的遗传原因，没有HSCR相关的突变是100%的渗透，这表明基因-基因和基因-环境的相互作用决定HSCR的发生。为了验证某些药物可能改变HSCR风险的假设，我们用人类妊娠早期常用的药物治疗斑马鱼，发现布洛芬导致远端肠中肠神经元HSCR样缺失。使用胎儿CF-1小鼠肠切片培养物，我们发现布洛芬处理的肠神经嵴衍生细胞（ENCDC）迁移减少，板状伪足减少，活性RAC 1/CDC 42水平降低。此外，抑制ROCK，一种RHOA效应子和已知的RAC 1拮抗剂，逆转了布洛芬对培养物中迁移小鼠ENCDC的作用。Icadine还抑制了体内ENCDC对Ret+/−小鼠肠道的定殖，并显著降低了培养物中鸡ENCDC对肠道的定殖。有趣的是，布洛芬不影响ENCDC迁移，直到暴露至少三小时后。此外，Ptgs 1（考克斯1）和Ptgs 2（考克斯2）缺陷的小鼠在体外具有正常的ENCDC肠道定植和正常的ENCDC迁移，表明COX非依赖性效应。与对ENCDC的选择性和菌株特异性作用一致，布洛芬不影响肠道间充质细胞、NIH 3 T3或WT C57 BL/6 ENCDC的迁移，也不影响斑马鱼背根神经节细胞前体的迁移。因此，布洛芬在体外抑制ENCDC迁移，在斑马鱼、小鼠和鸡体内抑制ENCDC的肠道定植，但存在细胞类型和菌株特异性反应。这些数据引起了人们的关注，布洛芬可能会增加一些遗传易感儿童的先天性巨结肠症风险。
Hirschsprung Disease (HSCR) is a potentially deadly birth defect characterized by the absence of the enteric nervous system (ENS) in distal bowel. Although HSCR has clear genetic causes, no HSCR-associated mutation is 100% penetrant, suggesting gene-gene and gene-environment interactions determine HSCR occurrence. To test the hypothesis that certain medicines might alter HSCR risk we treated zebrafish with medications commonly used during early human pregnancy and discovered that ibuprofen caused HSCR-like absence of enteric neurons in distal bowel. Using fetal CF-1 mouse gut slice cultures, we found that ibuprofen treated enteric neural crest-derived cells (ENCDC) had reduced migration, fewer lamellipodia and lower levels of active RAC1/CDC42. Additionally, inhibiting ROCK, a RHOA effector and known RAC1 antagonist, reversed ibuprofen effects on migrating mouse ENCDC in culture. Ibuprofen also inhibited colonization of Ret+/− mouse bowel by ENCDC in vivo and dramatically reduced bowel colonization by chick ENCDC in culture. Interestingly, ibuprofen did not affect ENCDC migration until after at least three hours of exposure. Furthermore, mice deficient in Ptgs1 (COX 1) and Ptgs2 (COX 2) had normal bowel colonization by ENCDC and normal ENCDC migration in vitro suggesting COX-independent effects. Consistent with selective and strain specific effects on ENCDC, ibuprofen did not affect migration of gut mesenchymal cells, NIH3T3, or WT C57BL/6 ENCDC, and did not affect dorsal root ganglion cell precursor migration in zebrafish. Thus, ibuprofen inhibits ENCDC migration in vitro and bowel colonization by ENCDC in vivo in zebrafish, mouse and chick, but there are cell type and strain specific responses. These data raise concern that ibuprofen may increase Hirschsprung disease risk in some genetically susceptible children.