258 Chapter 9 Burn injury is a prevalent cause of disability and mortality throughout the world and its consequences affect patients both physically and mentally. Over the years, it has become increasingly evident that the immune system plays an indispensable role in the (patho)physiological processes after burn injury. An improved understanding of the burn-induced immune response is necessary to limit secondary pathologies in patients with burns. The aim of this thesis was to improve our understanding of the immune response after burn injury by reviewing existing experimental data from literature and by investigating patient samples through advanced analysis of cells and inflammatory mediators. This knowledge was then used to develop skin models wherein aspects of burn wound healing and immune response can be studied in vitro without a need for animal experimentation. PART 1: IMMUNE RESPONSE IN ANIMAL BURN MODELS All available empirical evidence on immune reactions in animal burn models was comprised into two comprehensive systematic overviews, combining more than 500 individual studies. The compilation of these data improves accessibility to important findings, without a need to perform additional animal experiments. These reviews put in perspective the uncontrolled, hyperactive response of immune cells (Chapter 2) and inflammatory mediators (Chapter 3) that persists for weeks after burn trauma (Figure 1). Meta-analyses revealed that shortly after burn injury the numbers of immune cells (such as neutrophils, monocytes and thrombocytes) and many inflammatory mediators (e.g IL-1β, IL-6, TNF-α, CCL2, CXCL1, G-CSF and CRP) were increased in blood. In contrast, the number of lymphocytes and the level of IL-12 were reduced compared to healthy control animals. Burn wound tissue contained increased levels of several cytokines, chemokines and growth factors and surges of neutrophils and macrophages, whereas mast cell numbers first decreased and then increased after 2 weeks. Cell function was also affected as migration of leukocytes and inflammatory mediator production by neutrophils and macrophages were enhanced, while antibacterial activity of neutrophils was reduced. Subgroup analysis were performed to investigate differences between burn techniques and animal models. Furthermore, study quality, risk of bias and adherence to ARRIVE guidelines was discussed and the importance of complete reporting, correct use of nomenclature and effortless access to raw datasets emphasized. These reviews will help to improve future burn research into the post-burn immune response and can be used to design targeted interventions such as removal of inflammatory triggers, cytokine blockade or regulation of immune cells to improve burn treatment and outcome for patients.
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