Long-lasting effects of dexamethasone on immune cells and wound healing in the zebrafish

• Published in: Wound repair and regeneration 2015-11, Vol.23 (6), p.855-865
• Main Authors: Sharif, Faiza, Steenbergen, Peter J., Metz, Juriaan R., Champagne, Danielle L.
• Format: Article
• Language: English
• Subjects: Amputation, Traumatic - pathology; Animal Fins - pathology; Animals; Anti-Inflammatory Agents - pharmacology; Cell Proliferation - drug effects; Danio rerio; Dexamethasone - pharmacology; Disease Models, Animal; Freshwater; Larva; Macrophages - drug effects; Neutrophils - drug effects; Regeneration; Up-Regulation; Wound Healing - drug effects; Zebrafish - genetics
• ISSN: 1067-1927; 1524-475X
• DOI: 10.1111/wrr.12366

ABSTRACT 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.