The risk for infections and sepsis is dramatically increased for weeks after severe burn injuries and sepsis is the leading cause of death in patients with large burn injuries. Addressing septic complications early and effectively is critica for the survival of burn patients. However, differentiating sepsis from systemic inflammation response (SIRS) is a difficult and common clinical problem. We choose the neutrophils as the focus for our study, because they are the first cellular line of defense against infections, and finely tuned to respond to infections anywhere in the body. However, the neutrophils are well known to be severely affected after burn injuries, and thus measuring the functional status of neutrophils is a delicate task. Moreover, neutrophil functional assays are notoriously difficult to implement in the clinical setting, and traditional methods to measure neutrophil function are imprecise and prone to artifacts. In this study, we will address these limitations with the help of novel microfluidic technologies. In preliminary work we identified a unique pattern, of neutrophil spontaneous migration, that appears to be sensitive and specific for the occurrence of sepsis in patients with major burn injuries. In this study, we will further validate the utility of the spontaneous migration phenotype for the diagnostic, monitoring, and prediction of sepsis in patients with major burns, and also develop novel technologies to probe other essential functional of neutrophils during sepsis, including retrotaxis, extracellular trap release, and interactions with bacteria and fungi. Ultimately, our study will help identify useful relationships between neutrophils and the risk for infections and sepsis to guide the development of new therapeutic approaches targeting neutrophil functionality, to prevent septic complications in burn patients before they occur.
Sepsis is the leading cause of death in patients with large burn injuries and its treatment is usually focused on the use of proper antibiotics. However, the body owns resources, the neutrophils, are often ignored, even though evidence exists that this subpopulation of white blood cells is essential for protection against microbes and becomes progressively defective after burn injuries. In this proposal, we will employ novel microfluidic tools to probe the changes in neutrophil phenotype after burns, design new tools for measuring emerging neutrophil phenotypes, and monitor the interactions between neutrophils from patients and microbes in controlled conditions in vitro.
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