Despite major advances in the care of surgical patients suffering trauma from accidents or major surgery, postoperative sepsis remains a major cause of morbidity and mortality. One approach to address this problem is through a better understanding of the microbial recognition systems utilized by the host. These systems permit the host to efficiently clear microbes through the initiation of inflammatory mediator cascades. Many investigators have hypothesized that excessive or persistent activation of inflammatory signaling/mediator pathways contributes to end organ damage in sepsis. The investigators indicate that they have discovered that hepatocytes (HC) express high levels of the endotoxin (LPS) recognition molecule CD14. Furthermore, HC CD14 expression is markedly upregulated following endotoxemia or injury. Although leukocytes have been proposed as the primary source of CD14, the investigators posit that HC represent an important and previously unsuspected source of local and systemic CD14. Acting as an acute phase reactant, they hypothesize that the quantities of soluble CD14 released by HC are sufficient to mediate LPS interaction with CD14-negative cells in the periphery. Soluble CD14 concentrated in the liver should modulate the interaction of LPS with hepatic nonparenchymal cells. Finally, they provide evidence that HC can respond with changes in gene expression to physiologically relevant levels of LPS, and they propose that surface-expressed CD14 mediates this response. The investigators will pursue these hypotheses under two aims:
AIM I : To determine how CD14 is regulated and processed in hepatocytes. They will determine how CD14 is regulated at the transcriptional and posttranscriptional levels, which they believe will lead to a better understanding of how and when HC CD14 expression is increased. They also seek to establish how CD14 is differentially processed in HC to produce both membrane and soluble forms in studies which will quantitate how much CD14 is released from the liver.
AIM II : To determine the functions of hepatocyte-derived CD14.
Under Aim II, the investigators plan to utilize novel reagents (recombinant rat CD14, CD14-neutralizing antibodies, and CD14 knockout mice) to establish the functional roles of HC-derived CD14. They believe their results should yield key insights into strategies utilized by the host to respond to microbial invasion and the mechanisms leading to excessive activation of inflammatory mediator cascades.
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