Sepsis and septic shock are important clinical problems, with about 500,000 cases and $8 billion in health care costs annually. This problem is exacerbated within the intensive care setting and in immunocompromised patients Lipopolysaccharide (LPS), the endotoxic outer membrane component of Gram negative bacteria, has long been implicated as a major contributing factor to mortality in sepsis, due largely to the overproduction of inflammatory cytokines that is initiated by the interaction of LPS with host macrophages. To date, therapeutic intervention targeting either LPS or individual LPS-induced cytokines has been disappointing. Thus, an understanding of the mechanisms of LPS action at the molecular and cellular level remain a significant area of investigation. Pivotal to this understanding is a delineation of molecular mechanisms of """"""""early endotoxin tolerance"""""""" (EET), a well recognized, but poorly understood phenomenon that results in a state of refractoriness to subsequent LPS exposure. In vitro, a state of macrophage """"""""tolerance"""""""" to subsequent LPS stimulation can be achieved by pre-treatment of macrophages with LPS. Recent studies have provided strong support for the concept that """"""""tolerance"""""""" to some LPS responses is accompanied by increased activity as assessed by other LPS responses, thus leading to a more generalized concept of """"""""reprogramming."""""""" However, the relationship between EET in vivo and macrophage """"""""reprogramming"""""""" in vitro is not understood. This proposal details novel experimental approaches to define events that mediate EET. The overall hypothesis to be tested is that the initial interaction of LPS with host macrophages initiates a process of genetic """"""""reprogramming"""""""" via selective modulation of a cassette of pro- and anti-inflammatory mediator genes that, in turn, defines the EET phenotype. The investigators further hypothesize that products of genes selectively affected by """"""""reprogramming"""""""" profoundly influence the course of Gram negative infection.
Their Specific Aims are designed to (1) dissect the contribution of specific macrophage subsets and genes already implicated in this process, (2) identify novel genes that contribute to EET and to evaluate the impact of EET on sepsis, and (3) analyze specific intracellular pathways for their potential role in the induction/maintenance of """"""""tolerance."""""""" It is expected that, at the conclusion of this research, the mechanism of endotoxin tolerance and its potential impact on disease outcome in both sepsis and other diseases will be better understood.
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