Shock In Mice Research Articles

Nuclear factor of activated T cells transcription factor NFATp controls superantigen-induced lethal shock.

Tumor necrosis factor alpha (TNF-alpha) is the key mediator of superantigen-induced T cell lethal shock. Here, we show that nuclear factor of activated T cells transcription factor, NFATp, controls susceptibility to superantigen-induced lethal shock in mice through its activation of TNF-alpha gene transcription. In NFATp-deficient mice, T cell stimulation leads to delayed induction and attenuation of TNF-alpha mRNA levels, decreased TNF-alpha serum levels, and resistance to superantigen-induced lethal shock. By contrast, after lipopolysaccharide (LPS) challenge, serum levels of TNF-alpha and susceptibility to shock are unaffected. These results demonstrate that NFATp is an essential activator of immediate early TNF-alpha gene expression in T cells and they present in vivo evidence of the inducer- and cell type-specific regulation of TNF-alpha gene expression. Furthermore, they suggest NFATp as a potential selective target in the treatment of superantigen-induced lethal shock.

Compound 48/80, a histamine-depleting agent, blocks the protective effect of morphine against electroconvulsive shock in mice.

We have shown that morphine has an anticonvulsive effect against maximal electroconvulsive shock (MES) in mice, and this effect is antagonized by histamine H1-receptor antagonists. Brain histamine is localized both in neurons and in mast cells, and morphine is known to enhance the turnover of neuronal histamine and to release histamine from mast cells. In the present experiments, compound 48/80 was injected chronically (0.5 mg/kg on day 1, 1 mg/kg on day 2, 2 mg/kg on day 3, 3 mg/kg on day 4, and 4 mg/kg on day 5, twice daily, ip) to deplete mast cell contents. Morphine (0.001-10 mg/kg, ip; N = 20) produced a dose-dependent anticonvulsive effect against MES seizure in mice with non-depleted mast cells, whereas it did not exert any anticonvulsive effect in mice with depleted mast cells. These results indicate that morphine produces its anticonvulsive effect against maximal electroconvulsive shock in mice by liberating histamine from mast cells.

JTE-607, a novel inflammatory cytokine synthesis inhibitor without immunosuppression, protects from endotoxin shock in mice.

We investigated the effect of a novel N-benzoyl-L-phenylalanine derivative compound (JTE-607) on production of various cytokines and other immune responses in vitro and on endotoxin shock in vivo. Human, monkey, rabbit, mouse and rat peripheral blood mononuclear cells (PBMCs), and human fibroblasts, umbilical vein endothelial cells (HUVEC), mesangial cells and T cells were used in vitro. Endotoxin shock was induced by lipopolysaccharide (LPS) in Corynebacterium parvum (C. parvum) sensitized male C57BL/6 mice in vivo. JTE-607 inhibited inflammatory cytokine production, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8 and IL-10, from LPS-stimulated human PBMCs, with IC50 values of 11, 5.9, 8.8, 7.3 and 9.1 nM, respectively. The inhibitory effects of JTE-607 were also seen in mRNA expression of those cytokines. The potency of JTE-607 on cytokine production from PBMCs of other species, and from other human cells were much lower than that on human PBMCs. JTE-607 did not affect either LPS-stimulated microbead phagocytosis or reactive oxygen species production at 1 microM in human PBMCs but slightly suppressed expression of major histocompatibility complex class II antigen at 1 microM, although it was 100-fold less active than it was as a cytokine inhibitor. JTE-607 (0.3-10 mg/kg, i.v.) showed dose dependent inhibition of mortality after LPS challenge in C. parvum sensitized mice in accordance with a decrease of plasma TNF-alpha. These results suggest that JTE-607 is a multiple cytokine inhibitor specific for human PBMCs. This compound may be useful for the treatment of various cytokine mediated diseases such as septic shock without causing immunosuppression.

Pentoxifylline Inhibits Superantigen-Induced Toxic Shock and Cytokine Release

Tumor necrosis factor alpha (TNF-alpha) is a critical cytokine that mediates the toxic effects of bacterial superantigens like staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin 1 (TSST-1). Pentoxifylline, an anti-inflammatory agent that inhibits endotoxemia and lipopolysaccharide (LPS)-induced release of TNF-alpha, was tested for its ability to inhibit SEB- and TSST-1-induced activation of human peripheral blood mononuclear cells (PBMCs) in vitro and toxin-mediated shock in mice. Stimulation of PBMCs by SEB or TSST-1 was effectively blocked by pentoxifylline (10 mM), as evidenced by the inhibition of TNF-alpha, interleukin 1beta (IL-1beta), gamma interferon (IFN-gamma), and T-cell proliferation. The levels of TNF-alpha, IL-1alpha, and IFN-gamma in serum after an SEB or TSST-1 injection were significantly lower in mice given pentoxifylline (5.5 mg/animal) versus control mice. Additionally, pentoxifylline diminished the lethal effects and temperature fluctuations elicited by SEB and TSST-1. Thus, in addition to treating endotoxemias, the cumulative in vitro and in vivo data suggest that pentoxifylline may also be useful in abrogating the ill effects of staphylococcal enterotoxins and TSST-1.

Effect of lazaroid U-74389G and methylprednisolone on endotoxin-induced shock in mice

<h2>Abstract</h2> <b>Background:</b> Lazaroids are nonglucocorticoid analogs of methylprednisolone with multiple actions. We investigated whether lazaroid U-74389G could attenuate endotoxin-induced liver injury. We hypothesized that U-74389G treatment may protect against hepatic injury by suppressing proinflammatory gene up-regulation through inhibition of activation of nuclear factor κB (NF-κB). We also compared the efficacy of U-74389G with methylprednisolone in endotoxin-induced liver injury. <b>Methods:</b> Lipopolysaccharide (<i>Escherichia coli</i>, 30 mg/kg given intraperitoneally) was administered to male ICR mice, and U-74389G (3 mg/kg intraperitoneally) or methylprednisolone (30 mg/kg intravenously) was administered simultaneously. Phosphate-buffered saline solution (0.15 mL intravenously) was administered to mice that served as a control group. <b>Results:</b> U-74389G and methylprednisolone treatment significantly increased survival rates 48 hours after lipopolysaccharide injection and protected against lipopolysaccharide-induced liver injury in vivo, as indicated by the decreased hepatic lipid peroxidation, tumor necrosis factor-α, and inducible nitric oxide synthase messenger RNA formation, hepatic enzyme release, and neutrophil infiltration in the liver. U-74389G and methylprednisolone also showed inhibitory effects on NF-κB activation in the liver. <b>Conclusions:</b> These findings suggest that U-74389G can suppress proinflammatory gene up-regulation through inhibition of NF-κB activation and that it is a promising new antioxidant drug for the treatment of endotoxin shock. (Surgery 1999;125:421-30.)

Effect of lazaroid U-74389G and methylprednisolone on endotoxin-induced shock in mice

Background: Lazaroids are nonglucocorticoid analogs of methylprednisolone with multiple actions. We investigated whether lazaroid U-74389G could attenuate endotoxin-induced liver injury. We hypothesized that U-74389G treatment may protect against hepatic injury by suppressing proinflammatory gene up-regulation through inhibition of activation of nuclear factor κB (NF-κB). We also compared the efficacy of U-74389G with methylprednisolone in endotoxin-induced liver injury. Methods: Lipopolysaccharide ( Escherichia coli, 30 mg/kg given intraperitoneally) was administered to male ICR mice, and U-74389G (3 mg/kg intraperitoneally) or methylprednisolone (30 mg/kg intravenously) was administered simultaneously. Phosphate-buffered saline solution (0.15 mL intravenously) was administered to mice that served as a control group. Results: U-74389G and methylprednisolone treatment significantly increased survival rates 48 hours after lipopolysaccharide injection and protected against lipopolysaccharide-induced liver injury in vivo, as indicated by the decreased hepatic lipid peroxidation, tumor necrosis factor-α, and inducible nitric oxide synthase messenger RNA formation, hepatic enzyme release, and neutrophil infiltration in the liver. U-74389G and methylprednisolone also showed inhibitory effects on NF-κB activation in the liver. Conclusions: These findings suggest that U-74389G can suppress proinflammatory gene up-regulation through inhibition of NF-κB activation and that it is a promising new antioxidant drug for the treatment of endotoxin shock. (Surgery 1999;125:421-30.)

Protective effect of pentoxifylline plus thalidomide against septic shock in mice.

Mortality caused by septic shock in experimental animals is reduced by thalidomide, an inhibitor of tumour necrosis factor alpha. Another drug that could act on the pathophysiological mechanisms of septic shock is pentoxifylline, an inhibitor of platelet aggregation that increases the flexibility of the erythrocyte membrane and has fibrinolytic activity. We studied the effect of pentoxifylline alone and combined with thalidomide in septic shock; 97 NIH mice were injected with lipopolysaccharides of Salmonella abortus equi and D galactosamine. Animals were separated in 4 groups; group A (n = 20) was used as control, group B (n = 15) received thalidomide 50 mg/kg, group C (n = 20) received pentoxifylline 40 mg/kg, and group D (n = 15) received thalidomide plus pentoxifylline. Mortality was recorded every hour. Additionally, 5 animals from each group were sacrificed 8 h after the induction of septic shock for histological analysis of heart, lung, brain, kidney, small intestine, adrenal glands and liver. Microscopic findings were rated as absent, mild, moderate and severe damage. In control animals histological analysis showed intense haemorrhage and necrosis in all organs studied. When compared with controls, treatment with pentoxifylline plus thalidomide reduced mortality (P < 0.03). The tissue damage was less severe in animals from the groups that received pentoxifylline or pentoxifylline plus thalidomide (P < 0.05). Pentoxifylline seems to potentiate the beneficial effects of thalidomide, reducing mortality and attenuating the pathological changes produced by septic shock.

The Hypolipidemic and Anti‐Inflammatory Activity of BoronatedAromatic Amino Acids in CF1 Male Mice

The boronated aromatic amino acids were shown to be potent hypolipidemic agents in mice lowering both serum cholesterol and triglycerides after 16 days. Selective compounds were as effective as the clinical standards. Furthermore, the compounds were effective anti-inflammatory agents reducing local and central pain as well as suppressing LPS induced endotoxic shock in mice. These agents inhibited lysosomal and proteolytic enzymes of the liver and macrophages as a part of their mechanism of action.

Anticonvulsant effects of nimodipine and two novel dihydropyridines (PCA 50922 and PCA 50941) against seizures elicited by pentylenetetrazole and electroconvulsive shock in mice

In animal models of epilepsy, calcium entry blockers have shown anticonvulsant properties. We studied the antiepileptic effects of nimodipine and two novel dihydropyridines, a calcium antagonist (PCA 50922) and a calcium agonist (PCA 50941), on pentylenetetrazole seizure and maximal electroshock seizure (MES) in mice. Anticonvulsant profile of nimodipine and PCA 50922 was similar to that of clonazepam, but markedly different from that of phenytoin. None of the doses of the PCA 50941 showed anticonvulsant effect.

Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18)-derived peptide against murine endotoxemia.

CAP18 (an 18-kDa cationic antimicrobial protein) is a granulocyte-derived protein that can bind lipopolysaccharide (LPS) and inhibit various activities of LPS in vitro. The present study examined the protective effect of a synthetic 27-amino-acid peptide (CAP18(109-135)) from the LPS-binding domain of CAP18 against antibiotic-induced endotoxin shock, using highly LPS-sensitive D-(+)-galactosamine (D-GalN)-sensitized C3H/HeN mice. The antibiotic-induced endotoxin (CAZ-endotoxin) was prepared from the culture filtrate of Pseudomonas aeruginosa PAO1 exposed to ceftazidime (CAZ). Injection of CAP18(109-135) protected the mice injected with LPS or CAZ-endotoxin from death and lowered their tumor necrosis factor (TNF) levels in serum in a dose-dependent manner. Treatment with CAZ caused death of the D-GalN-sensitized P. aeruginosa PAO-infected mice within 48 h, while injection with CAP18(109-135) rescued the mice from death. In the mice rescued from death by injection with CAP18(109-135), endotoxin levels in plasma and TNF production by liver tissues were decreased but the numbers of viable infecting bacteria in their blood were not decreased significantly and remained at the levels in CAZ-treated mice. These results indicate that CAP18(109-135) is capable of preventing antibiotic-induced endotoxic shock in mice with septicemia and that the effect is due to its LPS-neutralizing activity rather than to its antibacterial activity.

Delayed and suppressed cytokine production in the liver is associated with lethal septic shock in mice infected with S. typhimurium

Delayed and suppressed cytokine production in the liver is associated with lethal septic shock in mice infected with S. typhimurium

Suppressive effects of antihistaminic and/or anti-PAF agents on passive anaphylactic shock in mice sensitized with allogeneic monoclonal IgE and IgG1 antibodies and hyperimmune serum

For the immunopharmacological characterization of murine passive anaphylactic shock, the effects of antihistaminics and/or anti-platelet-activating factor (anti-PAF) agents were studied on the shock mediated by allogeneic monoclonal IgE and IgG1 antibodies and hyperimmune serum. IgE antibody-mediated shock was strongly suppressed by cyproheptadine (10 mg/kg, ip) in every strain regardless of the age and sex of the mice and the presence or absence of a shock potentiator. As far as tested with CTS, DS, and B6D2F1 mice, IgE antibody-mediated shock was also suppressed by the other two antihistamines, triprolidine (10 mg/kg, ip) and oxatomide (100 mg/kg, Po). This type of shock was not suppressed by an anti-PAF agent, CV-6209 (3.3 mg/kg, iv), when tested on aged CTS mice given no shock potentiator and young DS mice given a potentiator such as Bordetella pertussis organisms or DL-propranolol. IgG1 antibody-mediated shock was also suppressed by cyproheptadine in general except for CTS mice. Suppression in the DL-propranolol-treated DS and C3H/He mice was not very marked on sensitization with undiluted or slightly diluted IgG1 ascites but quite striking on sensitization with properly diluted ascites. In contrast with the effect of cyproheptadine, suppression by CV-6209 was obvious in aged CTS mice but not in young DL-propranolol-treated DS mice. The shock in DL-propranolol-treated DS mice sensitized with undiluted or slightly diluted ascites was completely abolished by the combined use of these two agents. These results suggest that histamine and/or PAF play a major role in IgE antibody- and IgG1 antibody-mediated shock. However, so far as tested in young DS mice, the shock mediated by serum differed in drug susceptibility from that mediated by the monoclonal antibodies. In the absence of shock potentiators, prevention was produced by cyproheptadine in the males which had been sensitized with the 1:4 or 1:8 dilution of the immune serum. In the presence of DL-propranolol, prevention was not produced even by the combined treatment with cyproheptadine and CV-6209. Therefore, it is likely that some mediators other than histamine and PAF, whose release is triggered by antibody isotypes other than IgE and IgG1, play a greater role for the shock mediated by hyperimmune serum than for the shock mediated by IgE or IgG1 antibody, especially in the presence of shock potentiators.

Anti‐Inflammatory Activity of (Polyphenolic)‐Sulfonates and TheirSodium Salts in Rodents

A series of polyphenolic-sulfonated compounds were observed to have potent anti-inflammatory activity and were protective against induced endotoxic shock in mice at 8 and 16 mg/kg, I.P. These agents proved to be potent elastase inhibitors in human leukocytes and J774-AI and IC-21 mouse macrophages as well as prostaglandin cyclo-oxygenase inhibitors in J774-AI macrophages. The compounds from 5 to 50 μM inhibited TNFα release from IC-21 macrophages and IL-1 release from mouse P388D1 macrophages induced by LPS. The binding of these cytokines to high affinity receptors on target cells, e.g. L929 fibroblasts and IL-2 in HuT78 T lymphoma cells, were also suppressed by the agents. These compounds blocked the adhesion of leukocytes and macrophages to the plasma membranes of L929 fibroblasts.

Anti-allergic effects and oedema inhibition caused by the extract of Drymis winteri.

To study the acute anti-inflammatory and anti-allergic properties of an extract of D. winteri. Paw oedema induced in rats with various stimuli and anaphylactic shock in mice. The hydroalcoholic extract (HE) of D. winteri (Winteraceae) (30 to 100 mg/kg, p.o., 1 h prior) inhibited carrageenan (300 micrograms/paw) and dextran (100 micrograms/paw)-induced paw oedema formation in a dose-dependent manner, with mean ID50 values of 49 and < 30 mg/kg, respectively. The HE of D. winteri (30 to 100 mg/kg) also inhibited paw oedema induced by bradykinin (BK) (3 nmol), substance P (SP) (10 nmol) and PAF-acether (PAF) (10 nmol), in a dose-dependent manner, with mean ID50 values of 56, 63, and 58 mg/kg, respectively. However, the HE inhibited the rat paw oedema induced by prostaglandin E2 (PGE2) (10 nmol) (29 +/- 7 and 33 +/- 2% at 60 and 240 min) to a smaller extent, and had no effect on oedema elicited by histamine (100 nmol). In adrenalectomized animals, the inhibition by the HE of D. winteri (100 mg/kg, p.o., 1 h prior) of BK-elicited oedema (3 nmol/paw) was significantly smaller when compared with that observed in control animals. When assessed in rats actively sensitised to ovalbumin (OVO), the oedema caused by OVO (6 micrograms/paw) was significantly inhibited by HE of D. winteri (30 to 100 mg/kg, p.o.), with a mean ID50 of about 65 mg/kg. The HE of D. winteri (100 and 200 mg/kg, p.o.) significantly increased survival rate when assessed in anaphylactic shock in mice actively sensitised to the antigen. The protective effect was long-lasting, being observed for up to 15 h. Dexamethasone, used as positive control (0.5, 1 and 2 mg/kg) produced a long-lasting (up to 24 h) increase in the survival rate of the animals. These results confirm and extend our previous studies, and demonstrate the clear oral anti-inflammatory and anti-allergic properties of the active principle(s) present in the barks of D. winteri, thus confirming its reported medicinal use in folk medicine for the management of airway diseases.

Opioid-related changes in nociceptive threshold and in tissue levels of enkephalins after target disruption of the gene for neutral endopeptidase (EC 3.4.24.11) in mice

Neutral endopeptidase EC 3.4.24.11 (NEP) is localized in peptidergic neurons and various colocalized peptides or other humoral mediators may serve as substrates. Target disruption of the NEP gene was reported to enhance the lethal response to endotoxin shock in mice. We examined thermonociceptive thresholds and enkephalin (ENK) tissue levels in transgenic NEP (−/−) and control wild type NEP (+/+) mice. Hot plate (52°C) latency was 13.1±1.4 s in NEP (+/+) mice ( n=16) while latency increased significantly ( P=0.031) to 17.7±1.6 s in NEP (−/−) mice. Naloxone (10 mg/kg) had no effect on hot plate latency in NEP (+/+) mice (12.5 s, n=8), but significantly decreased the latency in NEP (−/−) mice compared to untreated NEP (−/−) deficient mice (10.5 s, n=8). Morphine (3 or 10 mg/kg) analgesic response was similar in knockout mice and wild type mice. Methionine-ENK (MET-ENK) and leucine-ENK (LEU-ENK) levels were determined in extracts from cortex, brain stem, hypothalamus, striatum, spinal cord, trigeminal ganglion and heart in treated and untreated mice. ENK-levels varied in a regionally-dependent manner and were significantly decreased in hypothalamus and spinal cord. We conclude that deletion of the NEP gene results in an opioid-related increase in thermonociceptive threshold. Regional differences in opioid metabolism indicate that NEP evokes tissue-specific patterns of ENK-regulation. NEP selectively controls opioid biosynthesis in hypothalamus and spinal cord presumably by feedback regulation.

Intervention in endotoxin shock by sulfatide (I3SO3-GalCer) with a concomitant reduction in tumor necrosis factor alpha production.

Accumulating evidence indicates that tumor necrosis factor alpha (TNF-alpha) is a principal mediator of endotoxin shock. We previously reported that the action as well as the production of TNF requires the adhesion of leukocytes to the endothelium through integrin beta2 and intercellular adhesion molecule 1. In order to elucidate the roles of the initial interaction of the leukocytes with the endothelium through the selectins, we have examined the effects of a ligand for L- and P-selectins, sulfatide, on endotoxin shock in mice. Consistent with previous reports, a single injection of a high dose of endotoxin caused acute lethality, marked hypotension, leukopenia, and elevation in serum TNF-alpha levels. Pretreatment with sulfatide prevented acute lethality and hypotension, but not leukopenia, with a concomitant reduction in the increase in serum TNF-alpha levels. Moreover, pretreatment with sulfatide inhibited lipopolysaccharide (LPS)-induced TNF-alpha production by a human monocytic cell line, THP-1, in a dose-dependent manner. These results suggest either that selectin is critically involved in conferring the responsiveness of leukocytes to LPS or that sulfatide interferes with the intracellular signaling pathway which leads to TNF-alpha gene activation.

CD28 ligation prevents bacterial toxin-induced septic shock in mice by inducing IL-10 expression.

The pathogenesis of septic shock is due mainly to bacterial toxin stimulation of the immune system, resulting in an excessive production of proinflammatory cytokines. TNF-alpha has been implicated as a major mediator in septic shock. Coinjection of D-galactosamine and LPS or staphylococcal enterotoxin B induced a rapid-onset, low-dose form of septic shock syndrome and ultimately led to death. We found that both the septic shock syndrome and death could be prevented by administration of anti-CD28 Ab. The protection induced by anti-CD28 Ab was associated with a decrease in TNF-alpha levels in the circulation. In addition, serum from anti-CD28 Ab-treated mice was capable of inhibiting the production of TNF-alpha by bone marrow-derived macrophages following treatment with LPS, indicating that anti-CD28 Ab induced production of soluble factors that subsequently inhibited the production of TNF-alpha. We confirmed that one of the factors present in serum was IL-10, because anti-CD28 Ab treatment stimulated the expression of IL-10, both in splenocytes and in T cell lines. Furthermore, injection of anti-IL-10 Abs could abolish the protective effect of anti-CD28 Ab on septic shock. Anti-IL-10 Ab could also suppress the anti-CD28 Ab-induced inhibition of TNF-alpha production, either in vivo or in vitro. Thus, we conclude that ligation of CD28 induces expression of IL-10, which in turn suppresses TNF-alpha production and prevents septic shock.

Induction of acute inflammatory lung injury by staphylococcal enterotoxin B.

Superantigens stimulate T lymphocytes at high frequency by interacting with appropriate Vbeta segments of the TCR. Challenge of mice with bacterial superantigens such as staphylococcal enterotoxin B (SEB) induces the systemic release of cytokines resulting in septic shock and death of sensitized animals. Analysis of putative pathogenic mechanisms of T cell-dependent septic shock revealed that administration of SEB results in acute inflammatory lung injury characterized by a profound increase in vascular permeability. Injury was associated with marked leukocyte infiltration of the lung and induction of cell adhesion molecules including VCAM-1, ICAM-1, and P-selectin, but not E-selectin. Lung infiltrating leukocytes consisted of granulocytes, mononuclear phagocytes and NK cells with granulocytes representing the major fraction. Consistent with a role of neutrophils as cellular mediators of inflammatory organ injury, we demonstrate activation of circulating granulocytes in mice treated with SEB. When compared with granulocytes of control mice, peripheral blood granulocytes of SEB-treated mice were found to express increased levels of cell surface Mac-1, to down-regulate expression of L-selectin, and to respond with an increased production of toxic oxygen metabolites upon exposure to FMLP. Interestingly, TNF-alpha further enhanced FMLP-induced oxidant production by granulocytes from SEB-treated but not control mice, suggesting that the systemic response to SEB increases granulocyte sensitivity to TNF-alpha-mediated signals. Together, these results suggest that acute inflammatory lung injury may contribute to the pathogenesis of T cell-dependent lethal shock in mice challenged with bacterial superantigens and indicate common pathogenic mechanisms of lung injury induced by a large number of distinct inflammatory stimuli.

Effect of antileukocyte adhesion molecule antibodies, nitric oxide synthase inhibitor, and corticosteroids on endotoxin shock in mice.

We compared the therapeutic effects of anti-leukocyte adhesion molecule antibodies (mAbs), a nitric oxide (NO) synthase inhibitor (monomethyl-L-arginine, NMLA), and methylprednisolone (MP) on experimental endotoxin-induced shock in mice. Lipopolysaccharide (LPS, 30 mg/kg) was administered to ICR mice intraperitoneally, While 1 mg/kg mAb, 5-20 mg/kg NMLA, or 30 mg/kg MP was administered intravenously. The placebo group received phosphate-buffered saline. The survival rate of the placebo group 48 h after LPS injection was 36%. The administration of anti-CD11a, anti-CD18, anti-lectin cell adhesion molecule-1 (anti-LECAM-1), and MP increased the survival rate to 70, 62, 64, and 100%, respectively; however, NMLA had no significant effect. A FACS analysis revealed that the CD18 expression of granulocytes increased 12-fold within 30 min after LPS administration. MP significantly suppressed its expression. The plasma level of nitrate/nitrite increased from 20 to 260 and 1000 microM 4 and 16 h, respectively, 20 mg/kg NMLA abolished NO production at 4 h, while MP inhibited it for up to 16 h. The hepatic malondialdehyde level increased from 0.50 to 2.46 nmol/mg protein at 4 h. Administration of anti-CD18 and MP reduced the level to 1.80 and 1.41 nmol/mg protein, respectively, whereas NMLA did not affect it. The mAbs and MP were concluded to be useful agents for endotoxin shock. The abolition of NO production had little influence on the hepatic cellular injury associated with endotoxemia.

Decreased production of interleukin-1-beta, prostaglandin-E2 and thromboxane-B2, and elevated levels of interleukin-6 and -10 are associated with increased survival during endotoxic shock in mice consuming diets enriched with sesame seed oil supplemented with Quil-A saponin.

Sesamin, present in sesame seed oil (SSO), can inhibit delta-5-desaturase activity and cause accumulation of dihomo-gamma-linolenic acid (DGLA), which displaces arachidonic acid, and subsequently decrease production of dienoic eicosanoids. The effects of diets containing both SSO and Quil A, a saponin that emulsifies fats and potentiates the immune responses, were also studied. A mixture of oils having a fatty-acid composition similar to that of SSO served as a control diet. The levels of docosapentaenoic acid in mice fed Quil-A-supplemented diets and of DGLA in those fed SSO diets were markedly higher in the liver. These changes were associated with a significant reduction in the plasma prostaglandin-E(1+2) and thromboxane-B2 levels in response to an intraperitoneal injection of a lethal dose of lipopolysaccharide (LPS) endotoxin (LD50 20 mg/kg). The levels of interleukin (IL-)6 were elevated and those of IL-1beta were decreased in mice consuming Quil-A-supplemented diets. The IL-10 levels that were elevated in all mice after LPS exposure, remained higher (even at 9 h) only in those fed Quil-A-supplemented diets, but declined rapidly in others. During a 48-hour observation period following LPS injection, all control animals died, and survival was 40% in the SSO group, and 27 and 50%, respectively, in those fed Quil-A-supplemented control and SSO diets. These data suggest that SSO and Quil A when present in the diet exerted cumulative effects that resulted in a decrease in the levels of dienoic eicosanoids with a reduction in IL-1beta and a concomitant elevation in the levels of IL-10 that were associated with a marked increase in survival in mice.