Bacterial sepsis and septic shock result from the overproduction of inflammatory mediators as a consequence of the interaction of the immune system with bacteria and bacterial wall constituents in the body. Bacterial cell wall constituents such as lipopolysaccharide, peptidoglycans, and lipoteichoic acid are particularly responsible for the deleterious effects of bacteria. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Within the circulation bacterial constituents interact with proteins such as plasma lipoproteins and lipopolysaccharide binding protein. The interaction of the bacterial constituents with receptors on the surface of mononuclear cells is mainly responsible for the induction of proinflammatory mediators by the bacterial constituents. The role of individual receptors such as the toll-like receptors and CD14 in the induction of proinflammatory cytokines and adhesion molecules is discussed in detail. In addition, the roles of a number of other receptors that bind bacterial compounds such as scavenger receptors and their modulating role in inflammation are described. Finally, the therapies for the treatment of bacterial sepsis and septic shock are discussed in relation to the action of the aforementioned receptors and proteins

The ATP-binding cassette transporter 1 (ABCA1) has recently been identified as a key regulator of high-density lipoprotein (HDL) metabolism, which is defective in familial HDL-deficiency syndromes such as Tangier disease. ABCA1 functions as a facilitator of cellular cholesterol and phospholipid efflux, and its expression is induced during cholesterol uptake in macrophages. To assess the role of macrophage ABCA1 in atherosclerosis, we generated lowdensity lipoprotein (LDL) receptor knockout (LDLr ؊/؊ ) mice that are selectively deficient in leukocyte ABCA1 (ABCA1 ؊/؊ ) by using bone marrow transfer (ABCA1 ؊/؊ 3 LDLr ؊/؊ ). Here we demonstrate that ABCA1 ؊/؊ 3 LDLr ؊/؊ chimeras develop significantly larger and more advanced atherosclerotic lesions compared with chimeric LDLr ؊/؊ mice with functional ABCA1 in hematopoietic cells. Targeted disruption of leukocyte ABCA1 function did not affect plasma HDL cholesterol levels. The amount of macrophages in liver and spleen and peripheral blood leukocyte counts is increased in the ABCA1 ؊/؊ 3 LDLr ؊/؊ chimeras. Our results provide evidence that leukocyte ABCA1 plays a critical role in the protection against atherosclerosis, and we identify ABCA1 as a leukocyte factor that controls the recruitment of inflammatory cells.

Septic shock is the most common cause of death in intensive care units and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived cytokines. Previously, we showed that apolipoprotein E (apoE), an established modulator of lipid metabolism, can bind LPS, thereby redirecting LPS from macrophages to hepatocytes in vivo. We now report that intravenously administered LPS strongly increases the serum levels of apoE. In addition, apoE can prevent the LPS-induced production of cytokines and subsequent death in rodents. Finally, apoE-deficient mice show a significantly higher sensitivity toward LPS than control wild-type mice. These findings indicate that apoE may have a physiological role in the protection against sepsis, and recombinant apoE may be used therapeutically to protect against LPS-induced endotoxemia.Sepsis is a syndrome referring to an exaggerated systemic response to infections, which can ultimately lead to death from septic shock. In fact, in the United States the incidence of sepsis has increased during the last decennia (1) and sepsis has become the most common cause of death in intensive care units, with 150,000 deaths annually (2, 3). Many cases of sepsis are caused by Gram-negative bacteria (1). Lipopolysaccharide (LPS), 1 a component of the outer membrane of these bacteria, is the primary cause of Gram-negative sepsis and gives rise to the same clinical features as are observed in patients with sepsis (3-6). Within the blood, the lipid A-moiety of LPS binds to the LPS-binding protein (7,8), and the resulting complex displays a high affinity for CD14-toll like receptor 4 (Tlr4) complex on mononuclear phagocytes (9, 10). Activation of these cells induces the release of inflammatory mediators such as tumor necrosis factor alpha (TNF␣) and interleukins (IL-1␣, IL-1␤, and IL-6). These cytokines are responsible for the metabolic and physiologic changes that ultimately lead to pathological conditions (11-13). The importance of these cytokines in LPS-induced death arises from observations that administration of TNF␣ or IL-1 to animals provokes a similar reaction as detected after injection of LPS (14 -17). In addition, antibodies against TNF␣ protect monkeys (18 -20), rabbits (21), and mice (17) against LPS-induced death. Also, blockade of IL-1 production prevents LPS-induced death of mice (22). Current therapeutic strategies are, therefore, directed against LPS (bactericidal/permeability-increasing protein (BPI), antibodies against LPS (23, 24)), cytokines (soluble TNF receptor, anti-TNF antibodies (25)), and receptors (soluble CD14, IL-1 receptor antagonist (26), antibodies against LBP), but the initial clinical data are merely disappointing.Lipoproteins are suggested to play an important role in the protection against infection and inflammation. All lipoproteins (high density lipoproteins (HDL), low-density lipoproteins (LDL), lipoprotein(a), very-low-density lipoproteins (VLDL), and chylomic...

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