Sharif Faiza, Steenbergen Peter J, Metz Juriaan R, Champagne Danielle L
Department of Integrative Zoology, Institute of Biology, Leiden University, The Netherlands.
Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information Technology, Lahore, Pakistan.
Wound Repair Regen. 2015 Nov-Dec;23(6):855-65. doi: 10.1111/wrr.12366.
This study assessed the lasting impact of dexamethasone (DEX) exposure during early development on tissue repair capacity at later life stages (5, 14, and 24 days post fertilization [dpf]) in zebrafish larvae. Using the caudal fin amputation model, we show that prior exposure to DEX significantly delays but does not prevent wound healing at all life stages studied. DEX-induced impairments on wound healing were fully restored to normal levels with longer post amputation recovery time. Further analyses revealed that DEX mainly exerted its detrimental effects in the early phase (0-5 hours) of wound-healing process. Specifically, we observed the following events: (1) massive amount of cell death both by necrosis and apoptosis; (2) significant reduction in the number as well as misplacement of macrophages at the wound site; (3) aberrant migration and misplacement of neutrophils and macrophages at the wound site. These events were accompanied by significant (likely compensatory) changes in the expression of genes involved in tissue patterning, including up-regulation of FKBP5 6 hours post DEX exposure and that of Wnt3a and RARγ at 24 hours post amputation. Taken together, this study provides evidence that DEX exposure during early sensitive periods of development appears to cause permanent alterations in the cellular/molecular immune processes that are involved in the early phase of wound healing in zebrafish. These findings are consistent with previous studies showing that antenatal course of DEX is associated with immediate and lasting alterations of the immune system in rodent models and humans. Therefore, the current findings support the use of the larval zebrafish model to study the impact of stress and stress hormone exposure in immature organisms on health risks in later life.
本研究评估了斑马鱼幼体在发育早期接触地塞米松（DEX）对其后期生命阶段（受精后5、14和24天[dpf]）组织修复能力的长期影响。使用尾鳍截肢模型，我们发现，预先接触DEX会显著延迟但不会阻止在所研究的所有生命阶段的伤口愈合。随着截肢后恢复时间延长，DEX诱导的伤口愈合损伤完全恢复到正常水平。进一步分析表明，DEX主要在伤口愈合过程的早期阶段（0-5小时）发挥其有害作用。具体而言，我们观察到以下事件：（1）大量细胞通过坏死和凋亡死亡；（2）伤口部位巨噬细胞数量显著减少且位置错误；（3）伤口部位中性粒细胞和巨噬细胞迁移异常和位置错误。这些事件伴随着参与组织模式形成的基因表达的显著（可能是代偿性的）变化，包括DEX暴露6小时后FKBP5的上调以及截肢后24小时Wnt3a和RARγ的上调。综上所述，本研究提供了证据表明，在发育的早期敏感时期接触DEX似乎会导致斑马鱼伤口愈合早期阶段所涉及的细胞/分子免疫过程发生永久性改变。这些发现与之前的研究一致，即啮齿动物模型和人类中，产前使用DEX的过程与免疫系统的即时和长期改变有关。因此，目前 的研究结果支持使用斑马鱼幼体模型来研究未成熟生物体中应激和应激激素暴露对后期生命健康风险的影响。
