Trauma is a major health problem with increasing morbidity, mortality and economic burdens. A common consequence of the initial injury is the development of sepsis, which, if not properly controlled, often develops into septic shock, multiple organ failure and death. Clinical studies have shown that cholesterol metabolism is altered during injury, which may contribute to a poor prognosis of the disease. However, the impact of cholesterol homeostasis on the response to injury has not been completely explored. The hypothesis to be tested is that changes in cholesterol homeostasis after injury affect the function of immune cells, especially macrophages, influencing the disease outcome. In particular, it is proposed that inflammatory mediators activate the expression of Cholesterol 25-hydroxylase (Ch25h), whose reaction product inhibits cholesterol biosynthesis. Then, cholesterol is mobilized from the plasma membrane into other subcellular compartments, which activates a sterol compensatory mechanism resulting in an increase in the expression of genes involved in the uptake of exogenous sources of lipids/cholesterol, including LDL receptor, Scavenger receptors and CD14. Since some of these receptors are involved in the innate immune response, their overexpression may prompt a hyper-inflammatory stage. In contrast, the reduction of plasma membrane cholesterol levels induces a decrease in the expression of Fc? receptors, causing a reduction in the clearance of pathogens. Therefore, the coincidence of a hyper-inflammatory stage and a low phagocytic condition produces a detrimental combination for injury resolution, which has a major impact in the outcome from the insult. This hypothesis will be investigated in isolated macrophages, septic mice induced by cecum ligation and puncture and isolated monocytes from burn injury patients. Finally, this application will address possible interventions directed at restoring cholesterol homeostasis and improving the outcome from injury.
Clinical studies have shown that cholesterol metabolism is modified during injury, and experimental results have indicated that changes in cholesterol homeostasis modulate the function of macrophages modifying the inflammatory response and affecting injury resolution. This investigation is directed at characterizing the mechanism involved in the interception between cholesterol homeostasis and macrophage contribution to injury resolution.
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