67 Review Inflammatory Mediators in Animal Burn Models Healing rate of burns is associated with wound depth Healing rate of the animal burn models was assessed over time by means of evaluating the percentage of remaining wound area (Figure 3). As burn injury is an acute type of trauma that generally heals within 4 weeks in rodents [19], we decided (post hoc) to categorize short time intervals early after burn followed by longer time intervals up to post burn day (PBD) 21, encompassing the different biological phases of wound healing: hemostasis, inflammation and proliferation. Categorization by wound depth showed a difference in wound healing rate. As expected, for deep dermal and especially fullthickness burn wounds the healing rate was slower than for partial-thickness burns. There was insufficient data available to assess the effect of variables such as TBSA, age or species on wound closure time. Figure 3. Healing rate of partial-thickness, deep dermal and full-thickness burn wounds in animal models. Measurements of re-epithelization and contraction were converted into remaining wound area. Data is presented as boxplots with median and quartiles. The number of studies is shown below the graph. Standardized mean difference could not be calculated for this type of measurement because control values are set at 100% without standard deviation. Burn injury increases levels of pro-inflammatory cytokines in blood and wound tissue Meta-analyses were performed on the effect of burn injury on the overall level of inflammatory mediators (Figure 4 and Supplementary Table 1). There was no significant indication of publication bias for these outcomes. Burn injury significantly increased systemic levels of IL-1β, IL-6, IL-10, IL-12p70, IL-17, IFN-γ, TNF-α, CXCL1 (GROα), CXCL2 (MIP-2), CXCL8 (IL-8), CCL2 (monocyte chemoattractant protein 1, MCP-1), granulocyte colony-stimulating factor (G-CSF), prostaglandin E2 (PGE2), TGF-β1, vascular endothelial growth factor (VEGF)-A, c-reactive protein (CRP), histamine, high mobility group box 1 (HMGB1) and nitric oxide (NO). In contrast to subunit IL-12p70, the level of IL-12 in blood was decreased after burn. Systemic levels of IL-2, IL-3, IL-4, IL-5, IL-13, CCL3 (macrophage 3
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