Endotoxemia endotoxins

TNF is produced and secreted by activated cells within minutes following contact with LPS, reaching peak levels at 90-120 minutes after the admnistration of Escherichia coli endotoxin in human volunteers (M27). Van Deventer et al. (D15) could not detect serum TNF levels during experimental endotoxemia. Even during continuous intravenous administration of recombinant TNF (rTNF), serum TNF rapidly becomes undetectable (M27). It has been proposed that circulating soluble TNF receptors (sTNF-Rs) may be an important down-regulating mechanism (G10). 

Relatively few data are available on the response of ANP to endotoxemia or septic shock. In an ovine model, a 13-fold increase in blood ANP concentration has been found 2 hours after endotoxin administration in a dose of 1.5 pg/kg body weight (LI7). The ANP level remained elevated during the first 6 hours and was associated with marked diuresis and natriuresis and with decreased cardiac output and increased peripheral resistence (LI7). In human studies, a significantly higher ANP blood level was observed in ARDS (E4) and in patients with acute respiratory failure associated with sepsis (M30). In a longitudinal study, we found that plasma ANP levels were increased in patients with sepsis, but the ANP levels showed no relation to the severity of disease or to the presence of shock (B8). 

Crouser, E.D., Julian, M. W., Blaho, D. V., and Pfeiffer, D. R., 2002a, Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity, Crit. Care Med. 30, pp. 276-284 Crouser, E.D., Julian, M. W., Huff, J. E., Joshi, M. S., Bauer, J. A., Gadd, M. E., Wewers, M. D., and Pfeiffer, D. R., 2004, Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia, Crit Care Med. 32, pp. 478-488... 

Endotoxin is present in both Gram-negative and Gram-positive infections (Marshall et al., 2004). The presence of endotoxemia in infections other than Gram negative likely reflects translocation of endotoxin across the gastrointestinal... 

Bunnell, E., Lynn, M., Habet, K., Neumann, A., Perdomo, C.A., Friedhoff, L.T., Rogers, S.L. and Parrillo, J.E. A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia. Crit Care Med 28 (2000) 2713-2720. 

There may be more than one cause for this syndrome. Complement activation by bioincompatible membranes (H4) hypersensitivity to the ethylene oxide used in dialyzer sterilization, to phthalic anhydride, or to isocyanates (plasticizers) used in potting compounds present in the dialyzer caps and entry of bacterial endotoxin from the dialysate into the bloodstream may each play a role (B22, H4, 12). Hypoxemia and high serum levels of the C3a and C5a complement fragments would suggest complement activation (C2, H4), and peripheral blood eosinophilia and high plasma IgE levels would point to a hypersensitivity reactions. Fever and chills, on the other hand, would incriminate endotoxemia. 

The other broad category of MSP actions on macrophages relates to mediator production. Endotoxin, or combinations of proinflammatory cytokines, causes expression of murine macrophage-inducible nitric oxide synthase, an effect that can be detected by Northern blots for the mRNA or by measurement of nitrate in the culture fluid. MSP prevents induction of NO-synthase by any of the above stimuli (Wang et al., 1994d). The inhibitory action of MSP is confined to this specific mediator. MSP did not inhibit endotoxin-induced expression of mRNA for monocyte chemoattractant protein-1. Furthermore, MSP caused secretion of IL-6 (but not IL-1 or TNFa) within 6 hr, and did not inhibit endotoxin-induced secretion of IL-1, IL-6, or TNFa (A. Skeel and E. J. Leonard, unpublished data). The in vitro modulation by MSP of endotoxin-induced NO production now has an in vivo counterpart. Concentrations of nitrate in serum of Stk / mice that received endotoxin intravenously were higher than in serum of comparably treated normal mice and at a critical endotoxin dose, only 20% of the Stk / mice survived, compared to 80% survival for normal mice (Correll et al., 1997). If MSP plays a role in the host response to endotoxemia, pro-MSP must be cleaved to biologically active MSP. Within 4 hr after i.v. administration of... 

The evidence incriminating TNF in the pathogenesis of septic shock is now considerable. However, other cytokines may be involved, perhaps in amplifying TNF production or responses. TNF induces IL-1 synthesis in macrophages and endothelial cells and IL-1 administration enhances the lethal effects of recombinant TNF (W2). More recently it has been shown that the administration of recombinant human IL-1 receptor antagonist IL-lra improves survival in lethal endotoxemia in mice (A12). Indeed the administration of endotoxin alone induces inhibitors of both TNF and IL-1 in human plasma (S48). These findings yet again underline the complexity of the network of cytokines and their inhibition. 

In anesthetized rats intravenous administration of Escherichia coli endotoxin induces a rapid (within 5 min) hypotension. Blood pressure then remains below the baseline value for several hours. In this model we previously established that the vascular hyporeactivity to norepinephrine and the fall in blood pressure occurring within 60 min of endotoxemia are mediated by an enhanced formation of NO following activation of ecNOS. In addition, prolonged periods of endotoxemia result in a significant induction of a calcium-independent NOS activity, which contributes to the vascular hyporeactivity to norepinephrine and the circulatory failure seen after prolonged periods of endotoxic shock (Szabo et ai, 1993a). 

TNF is a primary mediator of circulatory shock (Tracey et ai, 1986, 1987 for a review see Billiau and Vandekerchove, 1991). Administration of TNF alone or in combination with low (otherwise ineffective) doses of endotoxin, produces effects that, mimic several cardiovascular features of circulatory shock, including hypotension, peripheral vasodilatation, and organ damage (for a review see Billiau and Vandekerchove, 1991). Elevated plasma concentrations of TNF are found in endotoxemia (Beutler et al., 1985 Waage, 1987 Michieeta/., 1988 Feuerstein etal., 1990 Klosterhafen et ai, 1992). In addition, antibodies directed against TNF (Tracey et al., 1987 Mathison etal., 1988 Hinshaw etal., 1990 Silva etal., 1990 Walsh et al., 1992) or agents that inhibit the release of TNF, such as pentoxifylline (Schade, 1990), exert protective effects in animal models of endotoxin shock. 

Although the prevention of the endotoxin-induced circulatory failure with the above agents appears to be an important approach for the therapy of a variety of diseases, it should be stressed that the beneficial effects of these agents—when administered in animal models of circulatory shock after the initiation of endotoxemia—are limited (Tracey etal., 1987 Mathison et al., 1988 Hinshaw et al., 1990 Silva et al., 1990). For example, inhibition of iNOS induction with corticosteroids (Radomski et al., 1990 Knowles et al., 1990b) prevents the cardiovascular failure caused by endotoxin, but does not exert beneficial cardiovascular effects once iNOS induction has occurred (Wright et al., 1992 Paya et al., 1993). 

LPS-induced acute dermatitis Lung reperfusion injury IL-l/LPS-induced acute arthritis Immune complex-mediated acute glomerulonephritis PPD-induced delayed-type hypersensitivity Endotoxemia-induced ARDS-like lung injury Cerebral reperfusion injury Endotoxin-induced pleurisy Acid aspiration-induced lung injury... 

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