238 Chapter 8 Burn injury induces a multitude of reactions in the body that can become harmful to healthy tissues and even life-threatening [1]. The immune system is actively involved in wound healing processes, essentially to eliminate invading bacteria, remove damaged cells and ensure a timely recovery [2,3]. After burn injury, the immune system can be overstimulated by inflammatory triggers, leading to immune dysfunction and outof-control inflammation, that in turn slows down re-epithelization and remodeling processes of wound healing [4–6]. Information on response levels and the role of specific immune cells and associated inflammatory mediators during burn wound healing is still largely inadequate. With an improved understanding, treatment strategies can be developed to limit health complications that are a result of excessive inflammation in burn patients. Studies in burn patients are challenging due to the sudden onset, large variation between injuries, absence of baseline measurements and restrictions in sampling. Therefore, the majority of evidence originates from animal studies. This knowledge was, however, scattered over individual studies and could hardly be compared to the human situation [7,8]. The aim of this thesis was to improve our understanding of the immune response after burn injury. To reach this goal, we reviewed existing animal experimental data, and investigated immune cells and inflammatory mediators in patient samples using flow cytometry and multicolor microscopy. This knowledge was then used to develop skin models wherein the observed processes of burn wound healing and immune reactions can be studied without a need for animal experimentation. In this chapter, we discuss different facets of the burn-induced immune response and opportunities for improvement of burn research and treatment. BURN-INDUCED INFLAMMATORY MEDIATORS ATTRACT IMMUNE CELLS AND KEEP INFLAMMATION GOING As thermal injury destroys layers of the skin, it releases danger-associated molecular patterns (DAMPs) [9–11]. The immune system will be activated by DAMPs such as HMGB1 and IL-1α, and will send immune cells towards the site of injury [12,13]. Fibroblasts and keratinocytes that are stressed by the injury, as well as responding immune cells, will produce cytokines thereby influencing the intensity and duration of inflammation [14–17]. We investigated a large range of relevant inflammatory mediators in blood and wound tissue of both experimental animals (Chapter 2 and Chapter 3) and burn patients (Chapter 4 and Chapter 5), at a scale that has not been done before. This extensive, longitudinal analysis of the inflammatory mediators released upon burn injury provides a unique insight into inflammatory pathways activated by burn injury. For instance, we showed that neutrophil attractants and activators (HMGB1, IL-1β, IL-6,
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