A common and serious consequence of overwhelming bacterial infections is the development of septic shock and associated organ failure. The pathogenesis of the shock is presumed to be secondary to excessive stimulation of host cells by microbial constituents, which are potent activators of inflammatory cytokine synthesis. Although activation of cytokine synthesis is an important component of the innate immune response to infection, excessive cytokine production is likely an important mechanism of lethal septic shock. In the case of gram-negative sepsis, the pathogenesis of the shock is presumed to be secondary to excessive stimulation of host cells by bacterial lipopolysaccharide (LPS) endotoxin, a glycolipid that constitutes the major portion of the outermost membrane of gram-negative bacteria.<sup>56 Morrison D.C., Ryan J.L. Endotoxins and disease mechanisms Annu Rev Med 1987 ;  38 : 417  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 64 Raetz C.R.H. Biochemistry of endotoxins Annu Rev Biochem 1990 ;  59 : 129  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 65 Raetz C.R.H. Bacterial lipopolysaccharides: a remarkable family of bioactive macroamphiphiles Escherichia coli and Salmonella: Cellular and Molecular Biology Washington, DC: American Society for Microbiology (1996). 

Haga clic aquí para ir a la sección de Referencias</sup> This leads to the synthesis and release of proinflammatory cytokines, arachidonic acid metabolites, and various other mediators, which in turn mediate the systemic toxicity. LPS is an extremely potent toxin: macrophages can be activated at concentrations of LPS as low as 1 pg/mL. Despite the numerous medical advances that have occurred over the past 30 years, the outcome of gram-negative sepsis has remained relatively unchanged, with a mortality rate around 35%.<sup>57 Natanson C., Hoffman W.D., Suffredini A.F. , y al. Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis Ann Intern Med 1994 ;  120 : 771

Haga clic aquí para ir a la sección de Referencias</sup> Greater insight into the nature of host interactions with LPS is essential before we can hope to design effective antisepsis therapies.

The lipid A portion of LPS is conserved among gram-negative bacteria and appears to be responsible for the biologic toxicity of LPS.<sup>64 Raetz C.R.H. Biochemistry of endotoxins Annu Rev Biochem 1990 ;  59 : 129  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 66 Rietschel E.T., Brade H. Bacterial endotoxins Scientific American 1992 ;  267 : 26

Haga clic aquí para ir a la sección de Referencias</sup> Three cloned molecules expressed on the surface of monocytes and macrophages are known to bind the lipid A moiety of LPS. These include CD14, the macrophage scavenger receptor (SR), and the β2 (CD11/CD18) leukocyte integrins. The scavenger receptor does not appear to function as a signaling receptor for LPS, although studies of scavenger receptor knockout mice have demonstrated a role for the scavenger receptor in host defense.<sup>27 Haworth R., Platt N., Keshav S. , y al. The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock J Exp Med 1997 ;  186 : 1431  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 72 Suzuki H., Kurihara Y., Takeya M. , y al. A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection Nature 1997 ;  386 : 292  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> In contrast, both CD14<sup>32 Haziot A.A., Chen S., Ferrero E. , y al. The monocyte differentiation antigen, CD14, is anchored to the cell membrane by a phosphatidylinositol linkage J Immunol 1988 ;  141 : 547

Haga clic aquí para ir a la sección de Referencias, 93 Wright S.D., Ramos R.A., Tobias P.S. , y al. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein Science 1990 ;  249 : 1431

Haga clic aquí para ir a la sección de Referencias</sup> and CD11/18<sup>36 Ingalls R.R., Arnaout M.A., Golenbock D.T. Outside-in signaling by lipopolysaccharide through a tailless integrin J Immunol 1997 ;  159 : 433

Haga clic aquí para ir a la sección de Referencias, 37 Ingalls R.R., Golenbock D.T. CD11c/CD18, a transmembrane signaling receptor for lipopolysaccharide J Exp Med 1995 ;  181 : 1473

Haga clic aquí para ir a la sección de Referencias</sup> are capable of initiating intracellular signals, resulting in phagocyte activation, bacterial internalization (phagocytosis, endocytosis), and the activation of bactericidal defenses. In addition, CD14 and the CD11/CD18 integrins interact with LPS in conjunction with serum proteins, including soluble CD14 (sCD14) and LPS-binding protein (LBP). These soluble LPS receptors enhance the sensitivity of the membrane-bound receptors to LPS by 100- to 1000-fold.

In addition to the receptors described above, two additional ones, Toll-like receptor (TLR)-2 and TLR-4, have recently been implicated in LPS signaling. These human homologues of Toll, a protein first identified during the study of embryonic development in Drosophila melanogaster, have been linked to innate immunity and may play a role in the primitive activation pathway induced by LPS.