27 Review Immune Cells in Animal Burn Models INTRODUCTION Burn trauma often induces an overreaction of the immune system, known as systemic inflammatory response syndrome, which can cause damage to surrounding tissues and even distant organs [1,2]. Hyperactive inflammation and obstruction of wound healing can lead to excessive scarring [3] and psychological distress [4]. Information on the specific immune cells and inflammatory factors involved in the different phases of burn wound healing in humans is however scattered and incomplete. Human studies are limited by the absence of baseline values, heterogeneity among cases, and restrictions in (the timing of) blood and wound sampling. Animal experiments, executed in controlled and standardized settings [5], could improve our understanding of the mechanisms underlying the burn-induced immune response in humans. Undoubtedly, various genomic and physiological processes of the human response to trauma differ from that of animals, such as signaling pathways, wound contraction, and scar formation [6–8]. Nevertheless, animal studies contain valuable information that will improve our understanding of the cellular immune response to burn trauma. In this study, we aimed to identify the immune cells involved in the local and systemic inflammatory response to burn injury in animal models. Ultimately, we anticipate that this review leads to new perspectives in burn care and will support the improvement of treatment for patients. RESULTS Study selection, characteristics, and quality Our search generated 10,733 citations, of which 1,224 were considered relevant during title and abstract screening. From this selection, 111 studies were inaccessible, 247 were included in the systematic review (Figure 1), and 182 were used in meta-analyses (Supplementary File 1, Supplementary File 2). An overview of the study characteristics (Figure 2A-G) showed that most experiments were performed on young mice or rats. Full-thickness dorsal injury using hot water was the most common burn technique. It is worth noting that underreporting complicated the assessment of the overall study quality. Risk of bias (RoB) analysis showed that 33.5% of the included studies reported the use of randomization of animals before experimentation (Figure 2H). The majority of studies (94.0%) did not report the use of blinding, and a conflict-of-interest statement was present in 33.9% of the studies, in which four studies reported an actual conflict (Figure 2I,J). Overall, there was no significant indication of publication bias for the overall outcomes, but we did find a substantial risk of selection and performance bias. 2
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