63 Review Inflammatory Mediators in Animal Burn Models INTRODUCTION Burn injury is among the most challenging types of trauma in clinical practice, as it often causes life-threatening complications that include systemic inflammation, hypermetabolism and excessive scarring [1–4]. Overstimulation of the immune system can lead to a persistent surge of non-specific, innate immune cells that escalate inflammation and, paradoxically, can increase susceptibility to infection and reduce vaccine response [5,6]. The burn-induced immune response is characterized by a local and a systemic increase in inflammatory mediators, neutrophils, monocyte/macrophages and shifts in lymphocyte subsets [7–9]. The inflammatory mediators are important coordinators of cellular traffic and direct the immune response [10]. Patient’s recovery and overall outcome might be improved by immune modulation to limit tissue damage caused by a derailed and overactive immune system [11]. Detailed information on the involvement of specific cytokines, chemokines and growth factors during the post-burn immune response is warranted to re-balance profound immune dysregulation in patients. The absence of baseline values, variation among injuries and restrictions in the collection of blood and wound samples seriously hamper human burn research. Experimental animal models, which are more standardized and controllable, are an appealing alternative approach to study the underlying mechanisms of the burn-induced immune response [12]. However, our society strives to reduce, replace and refine animal experimentation because of ethical concerns and important genetic and physiological differences [13–15]. Systemic reviewing is a valuable method to synthesize an overview of empirical evidence from separate investigations, while contributing to reduction and refinement of animal experimentation and providing insights that might be relevant for clinical practice [16,17]. Previously, the burn-induced response of 14 different immune cell types in blood and wound tissue from experimental animals were analyzed in meta-analyses [8]. This review demonstrated a persistent presence of mainly neutrophils, monocytes and macrophages with altered functions, such as enhanced inflammatory mediator production. Immune cells produce inflammatory mediators to influence the intensity and direction of the immune response. In this systematic review, we generated an overview of the cytokines, chemokines and growth factors studied in experimental animal burn models. Overall study quality was assessed, and meta-analyses were performed to reveal the effect of burn injury on the level of inflammatory mediators present in blood and wound tissue. Furthermore, the temporal dynamics and role of wound severity, type of burn agent and differences in study models are demonstrated. This overview provides an excellent 3
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