Circulatory shock最新文献

Defective oxygen consumption and a pathological dependence of oxygen uptake on O2 supply have been considered important events in sepsis. To relate these features with tissue and mitochondrial metabolism, we studied oxygen uptake in whole isolated and perfused rat liver at two O2 supply levels, in the same liver slices, and in isolated liver mitochondria. Experimental sepsis in rats was induced by cecal ligation and double-gauge puncture. The results showed that liver and tissue slices from septic animals had a 60% greater O2 uptake than that of controls and that, during sepsis, liver O2 uptake was markedly dependent on O2 supply. Concomitantly, mitochondrial O2 uptake was nearly 30% greater with malate-glutamate as substrate, but not with succinate; lowering O2 concentration in the medium did not alter the enhanced function. In submitochondrial, only NADH-dehydrogenase activity was 100% higher in septic samples. At least, in some tissues, O2 dependence is a function of O2 availability, sensitized by increased mitochondrial O2 uptake related to changes in respiratory enzymes.

To determine the efficacy of low-volume resuscitation in dehydrated subjects, 7.5% hypertonic saline/6% dextran 70 (HSD) and lactated Ringer's (LR) treatments were compared in conscious pigs dehydrated for 48 hr prior to a 37% blood volume hemorrhage. Pigs randomized to treatment were resuscitated with equivalent sodium loads of either HSD (4 ml/kg) or LR (33.3 ml/kg) following the 60-min hemorrhage. Dehydration resulted in a 7-8% body weight loss. Mortality through 180 min of recovery was 1/13 (7.7%) for HSD, 1/11 (9.1%) for LR, and 4/8 (50%) for a group of dehydrated and untreated controls (DC). HSD and LR solutions elicited similar heart rate, cardiac output, arterial pressure, and oxygen transport responses in the recovery period following hemorrhage and resuscitation. HSD was as effective as LR in expanding plasma volume in dehydrated hemorrhaged pigs. Serum chemistries provided no evidence for a sustained systemic toxicity from HSD treatment. These findings support low-volume HSD resuscitation of hemorrhagic shock in moderately dehydrated subjects.

Bacterial lipopolysaccharide (LPS) stimulates the production and release of endogenous mediators [e.g., tumor necrosis factor (TNF), interleukins-1 and -6 (IL-1 and IL-6), and Platelet Activating Factor [PAF] responsible for the pathophysiologic changes and the mortality associated with sepsis. We recently demonstrated that lysozyme (LZM) bound to LPS (LZM-LPS complex) suppresses LPS-induced tumor necrosis factor-alpha (TNF-alpha) production in vivo. In the present study, we investigated the effect of LZM-LPS complex formation on LPS-induced IL-6 production, both in vitro and in vivo. With the addition of LZM-LPS complex, TNF-alpha and IL-6 release was significantly reduced compared with that by LPS in a dose-dependent manner in mouse macrophage-like cells, RAW264.7. IL-6 production in serum by LPS in carrageenan (CAR)-primed mice peaked at 2 hr following injection. LZM-LPS and LZM-Escherichia coli cell complex (as 1 microgram of LPS per mouse) released significantly reduced concentrations of IL-6 in serum (P < 0.01 and P < 0.001 versus CAR-pretreated LPS- or cell-injected mice). These results emphasize the important role of LZM in vivo in the neutralization of endotoxin. However, in the case of IL-6, by administration of a lethal dose of LPS (as 100 micrograms of LPS per mouse), the IL-6 level was reduced by LZM, but a significant concentration of IL-6 was still released; although the TNF- alpha concentration was negligible in this experimental condition. Thus, it is suggested that LZM might regulate the systemic inflammation induced during Gram-negative bacterial infections by inhibiting the release of cytokines in serum.

We previously reported that the endothelin-1 (ET-1)-induced increase in microvascular permeability in isolated rat lungs required leukocytes in the perfusate. The present study examines whether intravenous administration of ET-1 in rats causes an inflammatory reaction in the lungs. Histological examination of the lung specimens 2 hr following ET-1 infusion showed adhesion of leukocytes to the vascular endothelium in pulmonary vessels and sequestration of leukocytes in the pulmonary capillaries. Microscopic examination of the bronchoalveolar lavage fluid revealed that leukocytes had migrated into the alveoli. Simultaneously a depletion of peripheral blood leukocytes was observed. These effects were reversible by 24 hr. Monitoring of systemic hemodynamic effects showed a continued reduced cardiac stroke volume and increasing heart rate after 2 hr. In isolated rat lungs, ET-1 caused a rapid increase in pulmonary artery pressure, pulmonary microvascular pressure, and edema formation. Compared with Krebs-albumin-perfused lungs, blood-perfusion accelerated the edemagenic effect of ET-1. ET-1 plays a role in the regulation of leukocyte-endothelial cell interactions in the pulmonary circulation. This has potential importance for the edemagenic effect of ET-1.

The interactions of two anti-lipid A monoclonal antibodies (mAb)--HA-1A and SdJ5-1.17.15--with their antigenic sites on lipid A, were compared using a dot-blot assay and lipid A structural analogues, as well as lipid A-high-density lipoprotein (HDL) complexes. The reactivities of both mAb were affected by the type of fatty acid side chains and by the phosphate group on the glucosamine residue II; however, the interaction of SdJ5-1.17.15 appeared to be more markedly affected by the fatty acid side chains. A determination of the biological significance of these antigenic differences was made. Human peripheral blood mononuclear cells (hPBMC) challenged with Escherichia coli 055:B5 lipopolysaccharide (LPS) pre-incubated with SdJ5-1.17.15 released significantly less tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), compared to hPBMC exposed to vehicle preincubated LPS. HA-1A did not attenuate the in vitro release of either cytokine. The ability of both mAb to neutralize the in vivo toxicity of LPS was also evaluated. Rats administered E. coli 055:B5 pre-incubated with SdJ5-1.17.15 had a significantly reduced 24-hr mortality rate compared to vehicle controls. HA-1A did not attenuate the in vivo mortality rate. Therefore, the reactivity of anti-lipid A mAb with the antigen is preferentially affected by different residues on the lipid A moiety. Thus, the differences in biological activity seen with SdJ5-1.17.15 and HA-1A may be due in part to differences in their recognition sites on lipid A.

Three inhibitors of calcium-dependent cyclic adenosine 3'5'-monophosphate (cAMP) dependent phosphodiesterase IV (PDE IV) were evaluated for their effects on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production in vitro and in vivo and for their ability to protect mice from LPS-induced lethality in D-galactosamine (D-gal) sensitized mice. In vitro, on LPS-stimulated murine peritoneal macrophages (PEM), BRL 61063 (1,3-di(cyclopropylmethyl)-8-aminoxanthine) and rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) had similar TNF inhibitory activity with an IC50 ranging from 0.1 to 0.5 microM. Pentoxifylline (PTX), (3,7-dimethyl-1-(5-oxohexyl)xanthine) was less potent with an IC50 = 100 microM. In vivo, there was a rank order potency on serum TNF levels in LPS challenged D-gal sensitized mice. BRL 61063 inhibited TNF production with an ID50 of 0.1 mg/kg, rolipram at 1 mg/kg, and PTX at 200 mg/kg. Thus, BRL 61063 is 2,000 times more potent than PTX in reducing TNF serum levels in this model. Interestingly, TNF is implicated as having a central pathogenic role in the LPS/D-gal model, since survival of animals correlated directly with reduction of serum TNF levels for all three compounds tested. It is proposed that potent inhibitors of TNF may have therapeutic activity in disease states where TNF appears to play a role in the pathogenesis of the disease.

Whole blood from 10 healthy horses was aseptically collected into heparin or citrate anticoagulant and incubated in vitro for 6 hr in the absence (saline control) or presence of 1 ng endotoxin/ml blood. Pentoxifylline (0.1, 1, 10, or 100 micrograms/ml blood) was added 1 hr before, at the same time, or 1 hr after endotoxin. As compared to saline controls, pentoxifylline alone had no effect on mediator production, with the exception of significantly increasing 6-ketoprostaglandin F1 alpha concentration. Pentoxifylline inhibited endotoxin-induced increases in tumor necrosis factor (TNF) and interleukin-6 (IL-6) activity in a dose-related fashion, whether added before, at the same time, or after endotoxin. Pentoxifylline significantly inhibited tissue factor activity, but only when added before endotoxin. Pentoxifylline had no effect on endotoxin-induced 6-keto-prostaglandin F1 alpha production, but significantly inhibited thromboxane B2 (TxB2) production. The results of this study indicate that pentoxifylline, at blood concentrations consistent with those achieved in vivo, has effects that may be beneficial in the treatment of endotoxemia.

Therapy with anti-TNF antibody is reported to be effective in preventing morbidity and mortality in baboons given lethal infusions of Escherichia coli. Treated animals survived, and organ histopathology was absent when antibody was administered early after lethal infusions of E. coli. The present study explored the relationship between antibody dosage, pathophysiology, and survivability from shock. When antibody dose was decreased lungs, kidneys, adrenals, spleen, and liver were injured as shown by increased vascular congestion, hemorrhage, edema, and necrosis of tissues. Survival was also affected. All animals treated with 15 mg/kg antibody survived as reported earlier; less than 60% survived with 7.5 mg/kg; 9% survived with 5.0 mg/kg, and all died with 1.5 mg/kg. Serum concentrations of interleukin-6 (IL-6) increased markedly as dose of antibody decreased. The increases in concentrations of IL-6 were associated with increases in morbidity and mortality following E. coli administration.

The role of interleukin-6 (IL-6) in carbohydrate metabolism beyond its inhibition of hepatic phosphoenolpyruvate carboxykinase has not been widely pursued. To describe such IL-6 effects, we examined in the rat the responses of plasma corticosterone, glucagon, insulin, and glucose levels and the hepatic glycogen content 30, 60, 90, 120, and 180 min after intravenous injection of recombinant human IL-6. The effect to increase plasma corticosterone was consonant with the well-known action of IL-6 on the hypothalamus-pituitary-adrenal cortex. IL-6 produced a transient increase in plasma glucagon that was mirrored by elevated plasma glucose and a depletion of hepatic glycogen. Plasma insulin levels were not elevated within the first hour after IL-6 injection but were significantly elevated 90 min and beyond. We suggest that the stimulus for increased circulating insulin was elevated plasma glucose, rather than a direct effect of IL-6. The results demonstrate that IL-6, acting directly on peripheral organs and/or through the central nervous system (CNS) can alter the hormonal and carbohydrate milieu. We propose that these actions of IL-6 are one aspect of its role in the acute phase response.

We determined the efficacy of continuous arteriovenous hemofiltration (CAVH) in removing tumor necrosis factor (TNF), thromboxane A2, and prostacyclin, and in improving survival in endotoxemia. Twelve rats were given 10 mg/kg of E. coli 0:127:B8 lipopolysaccharide. Fifteen min later, the rats were randomized to ultrafiltered or non-ultrafiltered groups. Blood and ultrafiltrate were collected for TNF, thromboxane B2 (TxB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). After 4 hr, surviving rats were sacrificed. Five of 6 ultrafiltered and none of 6 non-ultrafiltered rats survived 4 hr. Plasma TxB2 > 1,000 pcg/ml and its rate of increase within the first 2 hr predicted death (P < 0.03). Ultrafiltration decreased the rate of rise in TxB2 (P < 0.04). Plasma TxB2 inversely correlated with TxB2 clearance by ultrafiltration. The concentration and rate of increase in TNF and 6-keto-PGF1 alpha did not predict survival. We conclude that CAVH improves short term survival in endotoxemia. Salutary effects appear to be due to thromboxane A2 removal.