Sepsis is a major cause of death in hospitalized patients. Lipopolysaccharide (LPS), an endotoxic component of gram negative bacteria, initiates an inflammatory cascade that contributes to multiple organ injury. Under inflammatory conditions, monocytes infiltrate the artery wall and differentiate to either dendritic cells (DCs) or macrophages (MF). Sepsis induces dysregulation of the innate immune response and changes in lipid metabolism leading to an increase in triglyceride (TG)-rich lipoproteins and a decrease in high density lipoprotein (HDL) levels in plasma. HDL and its major protein component apolipoprotein (apo) A-I exert prominent anti-inflammatory and anti-oxidant effects, and reduces injury responses associated with leukocyte adhesion to the vessel wall. Recently, there has been considerable interest in using HDL as a novel therapeutic agent for inflammatory diseases like sepsis. Although the mechanism of HDL action is not well understood, improving HDL quality/function may favorably influence the pathogenic response to sepsis. Recent studies from our laboratory show that a novel 18-residue peptide (4F), whose design is based on the structural features of apoA-I converts HDL from a dysfunctional to functional HDL form. 4F favors the formation of HDL particles enriched in apoA-I and paraoxanase-1 (PON1)/PAF-acetyl hydrolase (PAF-AH), enzymes that scavenge oxidized lipids and PAF. Exciting preliminary data show that 4F inhibits inflammation and cytotoxicity in both a rodent model of sepsis (cecal ligation and puncture model) and cell culture systems. In addition, it also plays a role in the differentiation of monocytes to DCs. 4F (like apoA-I) modulates monocyte/MF function and has potent anti-inflammatory activity. Based on pilot data, we hypothesize that 4F: (1) reduces vascular injury by inhibiting the association/binding of monocytes to ECs and/or their cytotoxic actions; and (2) improves the immune response by preferentially inducing the differentiation of monocyte/MF to DCs. It is further proposed that these effects are mediated both directly by the peptide and indirectly by improving HDL quality/function. To test these hypotheses, we propose the following specific aims: (1) to assess 4F-mediated changes in the quality/function of apo A-I and apoB-containing lipoproteins in a rodent model of sepsis (2) to determine whether anti-inflammatory mechanisms of 4F action in cell culture models are due to improvement in lipoprotein quality/function and/or direct protective effects of the peptide and (3) to determine whether 4F improves the immune response to sepsis by enhancing the formation of antigen-presenting dendritic cells. This proposal explores the role of apoA-I/HDL in the modulation of monocyte/MF function in the context of sepsis. Results of the proposed studies will provide new pharmacologic strategies for the treatment of sepsis and other pathological states characterized by reduced plasma HDL.
Sepsis is a major cause of death in hospitalized patients. Mortality is due, in large part, to the cellular injury induced by lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria. In this application, we propose to investigate whether the synthetic peptide 4F, which mimics the protective effects of HDL cholesterol, reduces inflammatory injury associated with sepsis. We hypothesize that this peptide exerts protective effects by stimulating the formation of new HDL particles with improved function and by direct effects on cells. Collectively, these effects serve to reduce cell injury induced by sepsis. ? ? ?
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