Research on (Isoniazid)－LTB－shock

TARGET-SYDROM RELATIONSHIP DRUG-TARGET-SYDROM RELATIONSHIP

Year Title Journal Abstract
2015Immunization with Heat Shock Protein A and γ-Glutamyl Transpeptidase Induces Reduction on the Helicobacter pylori Colonization in Mice.PLoS OneThe human gastric pathogen Helicobacter pylori (H. pylori) is a successful colonizer of the stomach. H. pylori infection strongly correlates with the development and progression of chronic gastritis, peptic ulcer disease, and gastric malignances. Vaccination is a promising strategy for preventing H. pylori infection. In this study, we evaluated the candidate antigens heat shock protein A (HspA) and H. pylori γ-glutamyl transpeptidase (GGT) for their effectiveness in development of subunit vaccines against H. pylori infection. rHspA, rGGT, and rHspA-GGT, a fusion protein based on HspA and GGT, were constructed and separately expressed in Escherichia coli and purified. Mice were then immunized intranasally with these proteins, with or without adjuvant. Immunized mice exhibited reduced bacterial colonization in stomach. The highest reduction in bacterial colonization was seen in mice immunized with the fusion protein rHspA-GGT when paired with the mucosal adjuvant LTB. Protection against H. pylori colonization was mediated by a strong systemic and localized humoral immune response, as well as a balanced Th1/Th2 cytokine response. In addition, immunofluorescence microscopy confirmed that rHspA-GGT specific rabbit antibodies were able to directly bind H. pylori in vitro. These results suggest antibodies are essential to the protective immunity associated with rHspA-GGT immunization. In summary, our results suggest HspA and GGT are promising vaccine candidates for protection against H. pylori infection.
2014A down-regulated epi-allele of the genomes uncoupled 4 gene generates a xantha marker trait in rice.Theor Appl GenetA γ-ray-induced xantha trait is epigenetically controlled by the genomes uncoupled 4 gene with enhanced promoter segment methylation and down-regulated expression in rice. For easy testing and to increase varietal purity, a xantha mutation (xnt), which turns plants yellow and makes them visually distinguishable from normal green rice, has been generated and bred into male sterile lines for hybrid rice production. The xnt locus was previously fine mapped to a ~100-kb interval on chromosome 11, but its identity was unknown. In this study, xnt was further narrowed down to a 57-kb fragment carrying eight opening reading frames (ORFs). All eight ORFs had identical genomic sequences and all but ORF2 (g enomes uncoupled 4, OsGUN4) had similar transcript abundance in the xantha mutant Huangyu B (HYB) and its parental variety Longtefu B (LTB). The expression of OsGUN4, however, was significantly reduced in HYB compared with LTB in terms of both transcript abundance (0.2% that of LTB) and expressed protein level (barely detectable in HYB but greater than the heat shock protein reference in LTB). Therefore, OsGUN4 was identified as the candidate gene underlying the xantha trait. The function of OsGUN4 in the xantha phenotype was confirmed by identification and characterization of new allelic OsGUN4 mutations. Comparative bisulfite genomic sequencing of OsGUN4 revealed increased methylation in a promoter region in the mutant, and the correlation between increased methylation and the xantha phenotype was further verified by demethylation treatment. In summary, we have identified an epi-allele of OsGUN4 as the causal gene of the xantha marker trait and revealed that enhanced methylation in its promoter down-regulated its expression in rice.
2014Immune responses of a chimaeric protein vaccine containing Mycoplasma hyopneumoniae antigens and LTB against experimental M. hyopneumoniae infection in pigs.VaccineA recombinant chimaeric protein containing three Mycoplasma hyopneumoniae antigens (C-terminal portion of P97, heat shock protein P42, and NrdF) fused to an adjuvant, the B subunit of heat-labile enterotoxin of Escherichia coli (LTB), was used to immunize pigs against enzootic pneumonia. The systemic and local immune responses, as well as the efficacy of the chimaeric protein in inducing protection against experimental M. hyopneumoniae infection were evaluated. In total, 60 male piglets, purchased from a M. hyopneumoniae-free herd, at 4 weeks of age were randomly allocated to six different experimental groups of 10 animals each: recombinant chimaeric protein by intramuscular (IM) (1) or intranasal (IN) (2) administration, commercial bacterin by IM administration (3), and the adjuvant LTB by IM (4, control group A) or IN (5, control group B) administration. All groups were immunized at 24 and 38 days of age and challenged at 52 days of age. The sixth group that was not challenged was used as the negative control (IN [n=5] or IM [n=5] administration of the LTB adjuvant). Compared with the non-challenged group, administration of the chimaeric protein induced significant (P<0.05) IgG and IgA responses against all individual antigens present in the chimaera, but it could not confer a significant protection against M. hyopneumoniae infection in pigs. This lack of effectiveness points towards the need for further studies to improve the efficacy of this subunit-based vaccine approach.
2013Glyburide, a K(+)(ATP)channel blocker, improves hypotension and survival in anaphylactic shock induced in Wistar rats sensitized to ovalbumin.Eur J PharmacolAllergens can induce anaphylactic shock and death due to serve hypotension. Potassium channel blockers (K(+)(ATP)) such as glyburide (GLY) induce vasoconstriction. The effect of (K(+)(ATP)) channel blockers on anaphylactic shock is poorly understood. Objective of the study was to test the hypothesis that GLY reduces hypotension induced in anaphylactic shock and increases survival. Rats were grouped into: G1-N=Naïve; G2-SC=Sensitized-Control; G3-SG=Sensitized-GLY (glyburide 40 mg/kg); G4-SE=Sensitized-EPI (epinephrine 10 mg/kg). G2 to G4 groups were sensitized with ovalbumin (OVA) and shock was induced by i.v. injection of OVA. Treatments were administered intravenously 5 min later. Mean arterial pressure (MAP), heart rate (HR), and mean survival time (MST) were measured for 60 min following OVA injection and treatments administration. At the end of the experiment, blood withdrawal was performed to measure plasma levels of histamine, leukotriene B(4) (LTB(4)), prostaglandin E(2) (PGE(2)) and prostaglandin F(2) (PGF(2)). Additionally blood gas (paO2, paCO2, SaO2) and electrolytes (Na(+), K(+) and Ca (++)) were measured. MAP was normal in G1-N; severe hypotension, negative inotropic and short MST were observed in G2-SC; normalization of MAP, with lesser negative inotropism and increased MST were observed in G3-SG; full recovery was observed in G4-SE. Histamine level was significantly higher in G2-SC; reduced in G3-SG and G4-SE. PGE(2) increased in G3-SG; PGF(2) increased in G2-SC and G3-SG. Na(+) and Ca (++) concentration decreased in sensitized rats but reversed in treated groups, without change in K(+) concentration. In conclusion, our data suggest that administration of GLY reduced hypotension and increases survival time in rat anaphylactic shock.
2013Cysteinyl leukotriene receptor antagonist montelukast ameliorates acute lung injury following haemorrhagic shock in rats.Eur J Cardiothorac SurgThe aim of this study was to assess the possible protective effect of montelukast against haemorrhagic shock-induced acute lung injury by interfering with inflammatory and oxidative pathways. Acute lung injury following haemorrhagic shock/resuscitation is an important contributor to late morbidity and mortality in trauma patients. Haemorrhagic shock (HS), followed by resuscitation, is considered to be an insult that frequently induces systemic inflammatory response syndrome and oxidative stress, resulting in multiple-organ dysfunction syndrome, including microvascular changes and microscopic damage termed acute lung paraynchymal injury. Montelukast is a cysteinyl leukotriene receptor antagonist that exerts an anti-inflammatory and antioxidant influence.Eighteen adult albino rats were assigned to three groups of six. In Group I, the 'sham' group, rats underwent all the surgical procedures but neither haemorrhagic shock nor resuscitation was carried out. Group II--the 'HS' induced, untreated group--was the control and underwent HS for one hour before being resuscitated with Ringer's lactate for one hour. Group III--the 'montelukast' group--underwent HS and treatment with montelukast (7 mg/kg i.p. injection) 30 min before the induction of HS, with the same dose repeated just before the reperfusion period. At the end of the experiment, two hours after completion of resuscitation, blood samples were collected for measurement of serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The trachea was then isolated and bronchoalveolar lavage was carried out for measurement of leukotriene B(4) (LTB(4)), leukotriene C(4) (LTC(4)) and total protein. The lungs were harvested and the left lung was homogenized for measurement of malondialdehyde (MDA) and reduced glutathione (GSH) and the right lung was fixed in 10% formalin for histological examination.Montelukast treatment (Group III) significantly reduced the total lung injury score, compared with the HS group (Group II) (P < 0.05). Montelukast also significantly decreased serum TNF-α and IL-6; lung MDA; bronchoalveolar lavage fluid (BALF) LTB(4), LTC(4) & total protein compared with the HS group (P < 0.05). Montelukast treatment significantly inhibited decrease in the lung GSH levels, compared with the HS group (P < 0.05).The results of the present study reveal that montelukast may ameliorate lung injury in shocked rats by interfering with inflammatory and oxidative pathways, implicating the role of leukotrienes in the pathogenesis of haemorrhagic shock-induced lung inflammation.
2012Hypertonic saline inhibits arachidonic acid priming of the human neutrophil oxidase.J Surg ResArachidonic acid (AA, and its leukotriene derivatives, e.g., LTB(4)) is an inflammatory mediator in post-shock mesenteric lymph that appears to act as an agonist on G-protein coupled receptors (GPCRs). These mediators prime neutrophils (PMNs) for an increased production of superoxide, implicated in the development of acute lung injury (ALI). Hypertonic saline (HTS) has also been shown to have immunomodulatory effects such as attenuation of PMN priming by precluding appropriate clathrin-mediated endocytosis of activated GPCRs, thereby potentially attenuating ALI. We hypothesize that HTS inhibits priming of the PMN oxidase by these lipid mediators.After PMNs were isolated from healthy donors, incubation was done in either isotonic buffer (control) or HTS (180 mmol/L) for 5 min at 37°C. The PMNs were then primed for 10 min with AA [5 μM] or 5 min with LTB(4) [1 μM] and the oxidase was activated with 200 ng/mL of phorbol 12-myristate 13-acetate (PMA), a non-GPCR activator, and superoxide anion generation was measured via reduction of cytochrome c.Both AA [5 μM] and LTB(4) [1 μM] significantly primed the PMA activated respiratory burst (P < 0.05, ANOVA, Newman-Keuls, n = 4). HTS inhibited both AA and LTB(4) priming of the respiratory burst.These data indicate that HTS reduces the cytotoxicity of PMNs stimulated by these lipid mediators in vitro and further support the immunomodulatory effects of HTS.
20112-(4-(Biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52)--a novel type of 5-lipoxygenase inhibitor with favourable molecular pharmacology and efficacy in vivo.Br J Pharmacol5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) representing a potential target for pharmacological intervention with inflammation and allergic disorders. Although many LT synthesis inhibitors are effective in simple in vitro test systems, they frequently fail in vivo due to lack of efficacy. Here, we attempted to assess the pharmacological potential of the previously identified 5-LO inhibitor 2-(4-(biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52).We evaluated the efficacy of HZ52 in vivo using carrageenan-induced pleurisy in rats and platelet-activating factor (PAF)-induced lethal shock in mice. We also characterized 5-LO inhibition by HZ52 at the cellular and molecular level in comparison with other types of 5-LO inhibitor, that is, BWA4C, ZM230487 and hyperforin.HZ52, 1.5 mg·kg⁻¹ i.p., prevented carrageenan-induced pleurisy accompanied by reduced LTB(4) levels and protected mice (10 mg·kg⁻¹, i.p.) against PAF-induced shock. Detailed analysis in cell-based and cell-free assays revealed that inhibition of 5-LO by HZ52 (i) does not depend on radical scavenging properties and is reversible; (ii) is not impaired by an increased peroxide tone or by elevated substrate concentrations; and (iii) is little affected by the cell stimulus or by phospholipids, glycerides, membranes or Ca²⁺.HZ52 is a promising new type of 5-LO inhibitor with efficacy in vivo and with a favourable pharmacological profile. It possesses a unique 5-LO inhibitory mechanism different from classical 5-LO inhibitors and seemingly lacks the typical disadvantages of former classes of LT synthesis blockers.
2009Pharmacological characterization of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), a novel selective 5-lipoxygenase-activating protein inhibitor that reduces acute and chronic inflammation.J Pharmacol Exp TherLeukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.
2008Brain Natriuretic Peptide (BNP) regulates the production of inflammatory mediators in human THP-1 macrophages.Regul PeptBrain Natriuretic Peptide (BNP), besides retaining vasodilatory, diuretic and natriuretic properties, is a vasoactive hormone that it is also involved in several cardiac diseases as well as severe sepsis and septic shock. All these conditions are characterized by an ongoing inflammatory response consisting in a complex interaction of pleiotropic mediators derived from plasma or cells, including monocytes and macrophages. However, the relationship between this hormone and inflammation remains to be elucidated. Therefore, the aim of the present study was to evaluate a possible BNP immunomodulatory activity on macrophages. Our results demonstrate that BNP regulates the production of major inflammatory molecules, such as reactive oxygen- and nitrogen species (ROS and RNS), leukotriene B(4) (LTB(4)), prostaglandin E(2) (PGE(2)); modulates the cytokines (TNF-alpha, IL-12 and IL-10) profile, and affects cell motility. These results furnish novel and brand-new proofs on BNP ability of modulating the production of inflammatory mediators in macrophages whose role has broad implications in inflammatory states where increased BNP levels have been reported.
2008Arachidonic acid in postshock mesenteric lymph induces pulmonary synthesis of leukotriene B4.J Appl Physiol (1985)Mesenteric lymph is the mechanistic link between splanchnic hypoperfusion and acute lung injury (ALI), but the culprit mediator(s) remains elusive. Previous work has shown that administration of a phospholipase A(2) (PLA(2)) inhibitor attenuated postshock ALI and also identified a non-ionic lipid within the postshock mesenteric lymph (PSML) responsible for polymorphonuclear neutrophil (PMN) priming. Consequently, we hypothesized that gut-derived leukotriene B(4) (LTB(4)) is a key mediator in the pathogenesis of ALI. Trauma/hemorrhagic shock (T/HS) was induced in male Sprague-Dawley rats and the mesenteric duct cannulated for lymph collection/diversion. PSML, arachidonic acid (AA), and a LTB(4) receptor antagonist were added to PMNs in vitro. LC/MS/MS was employed to identify bioactive lipids in PSML and the lungs. T/HS increased AA in PSML and increased LTB(4) and PMNs in the lung. Lymph diversion decreased lung LTB(4) by 75% and PMNs by 40%. PSML stimulated PMN priming (11.56 +/- 1.25 vs. 3.95 +/- 0.29 nmol O(2)(-)/min; 3.75 x 10(5) cells/ml; P < 0.01) that was attenuated by LTB(4) receptor blockade (2.64 +/- 0.58; P < 0.01). AA stimulated PMNs to produce LTB(4), and AA-induced PMN priming was attenuated by LTB(4) receptor antagonism. Collectively, these data indicate that splanchnic ischemia/reperfusion activates gut PLA(2)-mediated release of AA into the lymph where it is delivered to the lungs, provoking LTB(4) production and subsequent PMN-mediated lung injury.
2005Mechanisms of increased survival after lipopolysaccharide-induced endotoxic shock in mice consuming olive oil-enriched diet.ShockWe examined the impact of dietary fatty acid intake on lipopolysaccharide (LPS)-induced endotoxic shock. C57Bl/6J mice were fed for 6 weeks with a commercial laboratory chow (CC) or with test chows containing 7% (w/w) canola oil (CO), sesame oil (SeO), soybean oil (SO), or virgin olive oil (OO). The increase in body weight and energy consumption were similar for all diets tested. In the sixth week, mice were injected intraperitoneally with 400 microg of bacterial LPS to induce endotoxic shock. LPS induced a massive neutrophil infiltration into the peritoneal cavity and an increase in lipid body (LB) formation in leukocytes recovered from the peritoneal fluid of mice fed with CC, CO, SeO, or SO. In addition, there were increases in prostaglandin E(2) (PGE(2)), leukotriene B4 (LTB(4)), and cytokines IL-6, IL-10, and MCP-1 in peritoneal lavage, as well as in plasma TNF-alpha. In contrast, mice fed with OO exhibited reduced neutrophil accumulation and LB formation, and also had lower levels of PGE(2), LTB(4), MCP-1, and TNF-alpha. All mice fed with CC, CO, SeO, or SO died within 48 to 72 h after LPS injection. Interestingly, mice fed with the OO diet were resistant to endotoxic shock, with 60% survival at 168 h. These data indicate that intake of OO may have a beneficial role, reducing the magnitude of the inflammatory process triggered by endotoxic shock through modulation of LB formation and of the production of inflammatory mediators.
2004Inducible heat shock protein 70 kD and inducible nitric oxide synthase in hemorrhage/resuscitation-induced injury.Cell ResInducible head shock protein 70 kD (HSP-70i) has been shown to protect cells, tissues, and organs from harmful assaults in vivo and in vitro experimental models. Hemorrhagic shock followed by resuscitation is the principal cause of death among trauma patients and soldiers in the battlefield. Although the underlying mechanisms are still not fully understood, it has been shown that nitric oxide (NO) overproduction and inducible nitric oxide synthase (iNOS) overexpression play important roles in producing injury caused by hemorrhagic shock including increases in polymorphonuclear neutrophils (PMN) infiltration to injured tissues and leukotriene B(4) (LTB(4)) generation. Moreover, transcription factors responsible for iNOS expression are also altered by hemorrhage and resuscitation. It has been evident that either up-regulation of HSP-70i or down-regulation of iNOS can limit tissue injury caused by ischemia/reperfusion or hemorrhage/resuscitation. In our laboratory, geldanamycin, a member of ansamycin family, has been shown to induce HSP- 70i overexpression and then subsequently to inhibit iNOS expression, to reduce cellular caspase-3 activity, and to preserve cellular ATP levels. HSP-70i is found to couple to iNOS and its transcription factor. Therefore, the complex formation between HSP-70i and iNOS may be a novel mechanism for protection from hemorrhage/resuscitation-induced injury.
2003Omega-3 vs. omega-6 lipid emulsions exert differential influence on neutrophils in septic shock patients: impact on plasma fatty acids and lipid mediator generation.Intensive Care MedTo compare the effects of a conventional omega-6 lipid infusion and a fish oil based (omega-3) lipid infusion for parenteral nutrition on neutrophil function, lipid mediators, and plasma free fatty acids.Open-label, randomized, pilot study in a university hospital medical intensive care unit and experimental laboratory.Ten patients with septic shock and eight healthy controls.Patients (five per group) requiring parenteral nutrition received intravenously either a omega-3 or a omega-6 lipid emulsion for a 10-day period.At baseline levels of plasma free fatty acids were elevated several-fold, including high concentrations of the omega-6 lipid precursor arachidonic acid (AA). Neutrophils isolated from septic patients displayed markedly reduced responsiveness to ex vivo stimulation, including lipid mediator generation [leukotrienes (LT), PAF], respiratory burst, and phosphoinositide hydrolysis signaling. Under the omega-6 lipid infusion regimen abnormalities in plasma free fatty acids and impairment of neutrophil functions persisted or worsened. In contrast, a rapid switch in the plasma free fatty acid fraction to predominance of the omega-3 acids eicosapentaenoic acid and docosahexaenoic acid over AA occurred in response to omega-3 lipid infusion. LTB(5), in addition to LTB(4), appeared upon neutrophil stimulation originating from these patients, and neutrophil function was significantly improved in the omega-3 lipid group.omega-3 vs. omega-6 lipid emulsions differentially influence the plasma free fatty acid profile with impact on neutrophil functions. Lipid-based parenteral nutrition in septic patients may thus exert profound influence on sequelae and status of immunocompetence and inflammation.
2001Crystal structure of human leukotriene A(4) hydrolase, a bifunctional enzyme in inflammation.Nat Struct BiolLeukotriene (LT) A(4) hydrolase/aminopeptidase (LTA4H) is a bifunctional zinc enzyme that catalyzes the biosynthesis of LTB4, a potent lipid chemoattractant involved in inflammation, immune responses, host defense against infection, and PAF-induced shock. The high resolution crystal structure of LTA4H in complex with the competitive inhibitor bestatin reveals a protein folded into three domains that together create a deep cleft harboring the catalytic Zn(2+) site. A bent and narrow pocket, shaped to accommodate the substrate LTA(4), constitutes a highly confined binding region that can be targeted in the design of specific anti-inflammatory agents. Moreover, the structure of the catalytic domain is very similar to that of thermolysin and provides detailed insight into mechanisms of catalysis, in particular the chemical strategy for the unique epoxide hydrolase reaction that generates LTB(4).
2000Cell surface presentation of recombinant (poly-) peptides including functional T-cell epitopes by the AIDA autotransporter system.FEMS Immunol Med MicrobiolFor the efficient surface presentation and release of virulence factors especially pathogenic Gram-negative bacteria have developed several distinct secretion mechanisms. An increasing number of pathogens in various species employs a mechanism denoted the 'autotransporter' pathway. This pathway is characterised by an outer membrane translocator module representing the C-terminal domain of the transported protein itself. An intriguing potential application of such systems involves the transport and surface expression of recombinant proteins or peptides, like e.g. the presentation of antigens for the generation of live oral vectors as vaccine carriers. Here we report on the incorporation of heterologous (poly-) peptides in permissive sites of the translocator module of the adhesin-involved-in-diffuse-adherence (AIDA) autotransporter system. We demonstrate the presentation of the B subunit of the heat labile enterotoxin of Escherichia coli (LTB) as well as of functional T-cell epitopes of Yersinia enterocolitica heat-shock protein 60 (Y-hsp60) on the surface of E. coli.
1992Interactions between platelet activating factor and eicosanoids during endotoxic shock in anaesthetized pigs.Mediators InflammThe effects of platelet activating factor (PAF) on eicosanoid release during endotoxic shock was investigated in anaesthetized pigs receiving 5 mug kg(-1) Escherichia coli endotoxin (LPS) into the superior mesenteric artery over a 60 min period, by measuring plasma levels of a variety of mediators. Fifteen of the 31 animals infused with LPS and not treated with BN 52021, a PAF receptor antagonist, died within 30 min after the commencement of LPS infusion (non-survivors), while the other 16 survived the experimental period of 3 h, though in a state of shock (survivors). No alterations were observed in plasma concentrations of eicosanoids in the non-survivors. A significant, though transient, increase in eicosanoid concentrations occurred only in the survivors. Treatment with BN 52021 (4 mg kg-1, i.v.) injected 5 min prior to LPS infusion, failed to exert any effect on the survival rate. However, pretreatment with BN 52021 prevented circulatory collapse in the survivors and reduced the concentration of cyclooxygenase enzyme products, without affecting LTB(4) release. Exogenous administration of PAF (0.01 mug kg(-1)) caused hypotension and increased TXB(2) levels although 6-keto PGF(1alpha) and LTB(4) concentrations were unchanged. The data suggest that prostanoid formation may be secondary to PAF release in circulatory collapse evoked by LPS infusion in survivors, and give further support to the suggestion that PAF prostanoid interaction is important during endotoxic shock. However, their role in early death seems to be negligible, indicating the importance of other mediators.