Gram negative sepsis is initiated by host exposure to endotoxin (LPS), which triggers both pro-inflammatory and regulatory responses. Whereas neutrophils and macrophages are stimulated to release cytokines (TNF, IL-1), nitric oxide and other promoters of inflammation, sepsis also induces the acute phase response, wherein hepatocytes secrete substances designed to limit the extent and severity of the inflammatory reaction. Therefore, the balance between these opposing responses defines the difference between a healthy, protective reaction versus a pathologic, potentially fatal one. Despite increasing insight into the pathophysiology of gram negative infection, sepsis remains a significant problem in Medicine, annually effecting 500,000 patients and causing over 150,000 deaths. Unfortunately, recent clinical trials employed a strategy of inhibiting a single inflammatory mediator with anti- endotoxin or anti-cytokine agents, and have been largely unsuccessful. Efforts in our laboratory have focused on understanding the molecular basis of the """"""""lipemia of sepsis,"""""""" a facet of the acute phase response resulting from the increased production of triglyceride (TG)-rich lipoproteins by the liver. We hypothesize that chylomicrons (CM) and VLDL are components of an innate host immune response to infection. Specifically, CM and VLDL bind LPS forming lipoprotein-LPS complexes which are capable of regulating the hepatocellular response to inflammatory stimuli. Studies proposed herein will detail how the CM- LPS complexes are internalized and the impact of this cytoplasmic LPS on hepatocellular function. We will: (1) use our recently developed cell culture system to delineate the mechanisms by which CM-bound LPS is internalized by and inhibits the response of hepatocytes to cytokines, (2) determine the effect of CM-bound LPS on the response of hepatocytes to acute cellular stressors, and (3) determine whether CM- bound LPS inhibits cytokine-induced activation of hepatocytes by interrupting intracellular signal-transduction. Whereas the acute inflammatory response is critical for the host to combat bacterial infections, this defensive response must be tightly regulated or it can culminate in shock, multiple organ failure and death. Understanding how CM protect against LPS and contribute to host homeostasis is central to our understanding of the host response to infection, and the future development of a novel therapeutic strategy based on manipulating the response of target cells to pro-inflammatory stimuli rather than blocking individual inflammatory mediators.
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