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PubMed1988

Endotoxin causes neutrophil-independent oxidative stress in rats.

Endotoxin-induced oxidative stress is investigated in rats by measuring changes in plasma and lung tissue levels of glutathione disulfide (GSSG) using a modified enzymatic assay that allows simultaneous measurement of up to 80 samples. Salmonella enteritidis endotoxin (2 and 20 mg/kg) acutely increased both plasma reduced glutathione and GSSG with a rise in the ratio of GSSG to total glutathione. This increase in GSSG was enhanced by pretreatment with 1,3-bis(2-chloroethyl)1-nitrosourea (BCNU), an inhibitor of the glutathione reductase enzyme. However, there was no significant arteriovenous difference in plasma GSSG across the lung, and lung tissue GSSG did not increase after endotoxin treatment. The increase in plasma GSSG was not blocked by vinblastine-induced neutropenia and could not be reproduced by incubating rat blood in vitro with endotoxin. Receptor antagonists of platelet-activating factor (PAF), at a dose that previously inhibited endotoxin-induced lung injury, attenuated the endotoxin-induced increase in plasma GSSG. We conclude that endotoxin causes neutrophil-independent oxidative stress in rats, which may be enhanced by the action of platelet-activating factor.

Animals↗
PubMed1989

Endotoxin-pretreated neutrophils increase pulmonary vascular permeability in dogs.

Endotoxin causes pulmonary vascular neutrophil sequestration and injures the lung. Whether this is primarily due to a direct effect of endotoxin on the endothelium or is mediated by an action on the neutrophil is unclear. Canine neutrophils, isolated on plasma-Percoll gradients in vitro, were incubated with Salmonella enteriditis endotoxin, washed, and injected via wedged pulmonary arterial catheters into discrete lung zones of anesthetized dogs, whereas untreated neutrophils were administered into contralateral control lung zones. 113mIn-transferrin was administered intravenously 2 h before the animals were killed. Morphometry and extravascular protein accumulation were assessed at 4 h. Endotoxin treatment of neutrophils ex vivo induced a two- to three-fold increase in neutrophils in these lung zones (0.096 +/- 0.012 vs. 0.05 +/- 0.002 neutrophils/alveolar septal intercept, P less than 0.05). Extravascular-to-intravascular protein ratios in zones receiving endotoxin-treated neutrophils were significantly increased compared with control zones (0.146 +/- 0.02 vs. 0.079 +/- 0.02, P less than 0.05). Because complement fragments increase injury to endothelium in vitro, exogenous C5 fragments were administered to other dogs before administration of neutrophils but failed to significantly increase the extravascular protein signal (0.154 +/- 0.03 vs. 0.124 +/- 0.04). In summary, endotoxin treatment of neutrophils leads to neutrophil sequestration and increased pulmonary extravascular protein accumulation. C5 fragments failed to further enhance the protein accumulation. These data are consistent with an effect of endotoxin on the neutrophil to initiate neutrophil-endothelial interaction and subsequent lung injury.

Animals↗
PubMed1989

Endotoxin-induced lung injury in rats: role of eicosanoids.

We studied lung vascular injury and quantitated lung eicosanoids in rats after intraperitoneal injection of Salmonella enteritidis endotoxin. Within 40 min after endotoxin injection (20 mg/kg), lung tissue thromboxane B2 doubled, although 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) increased by 8- to 10-fold. Lung 5-hydroxyeicosatetraenoic acid and leukotriene C4 were variably increased by endotoxin. The levels of all eicosanoids returned to base line 6 h after endotoxin challenge. Lung vascular injury, as assessed by the extravascular accumulation of 125I-albumin and water in isolated perfused lungs, was observed 90 min after endotoxin injection (0.02-20 mg/kg) in vivo. Inhibition of the cyclooxygenase pathway with indomethacin and the lipoxygenase pathway with diethylcarbamazine and 2-(12-hydroxydodeca-5,10-dinyl)-3,5,6-trimethyl-1,4-benzoqui none failed to attenuate endotoxin-induced lung injury. In addition, essential fatty acid deficiency, which markedly reduced lung tissue levels of 6-keto-PGF1 alpha, thromboxane B2, and leukotriene C4, did not protect against endotoxin injury. We conclude that although lung eicosanoids are activated during endotoxemia, they do not play a crucial role in the development of acute lung vascular injury in rats.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Compartmentalization of the acute cytokine response in humans after intravenous endotoxin administration.

Lung cytokine production was examined after the intravenous administration of endotoxin to 23 normal human subjects. Bronchoalveolar lavage (BAL) was performed 7 days before and 1.5 or 5 h after endotoxin (4 ng/kg). Cytokine mRNA was evaluated in cell pellets (> 98% macrophages) by use of reverse transcription and the polymerase chain reaction. Immunoreactivity was measured by enzyme-linked immunosorbent assay of 20- to 40-fold concentrated BAL. Interleukin- (IL) 8 was detected in BAL (4-130 pg/ml) but not in the serum at baseline. Few neutrophils were found in BAL (< 1%) despite this IL-8 gradient. Peak serum IL-8 levels occurred 2 h after endotoxin (3,930 +/- 241 pg/ml), but BAL neutrophils and IL-8 did not increase. Peak serum tumor necrosis factor (TNF) levels occurred 1.5 h after endotoxin (1,844 +/- 210 pg/ml), but TNF was detected in only 1 of 20 BAL samples. TNF and IL-8 mRNA were detected by polymerase chain reaction in > 70% of the BAL samples before endotoxin, whereas IL-1 alpha, IL-1 beta, and IL-6 were detected in < 25% of the BAL samples. After endotoxin, no change was detected in cytokine mRNA expression. Actinomycin D treatment of the BAL did not alter the pattern of cytokine mRNA expression. These data suggest that mechanisms exist to insulate the alveolar space from the stimulatory effects of endotoxin and high circulating levels of cytokines. Additional factors appear to control the chemotactic effects of IL-8 on neutrophils in the air spaces during acute systemic inflammation.

Actins↗
PubMed1994

Loss of endothelium-dependent vasodilation in the pulmonary vessels of sheep after prolonged endotoxin.

We examined the hemodynamic response of awake sheep to prolonged endotoxin infusion (10 ng.kg-1 x min-1 for 12 h) and the in vitro endothelium-dependent relaxation of pulmonary arterial vessels excised 12 h after the end of endotoxin infusion to determine whether the development of pulmonary hypertension after endotoxin is associated with loss of endothelium-dependent relaxation. In seven of nine sheep, there was a maintained increase (4-68% of baseline) in pulmonary arterial pressure 24 h after the beginning of endotoxin infusion. The greater the increase in pulmonary arterial pressure in vivo, the greater was the in vitro deficit in endothelium-dependent relaxation of the pulmonary vessels. The maximum in vitro vessel dilation was 59% for pulmonary artery rings isolated from sheep without a sustained increase in pulmonary arterial pressure 24 h after endotoxin. Prolonged endotoxin infusion did not alter the in vitro response of pulmonary arterial vessels to KCl or 10(-5) M norepinephrine. Force development, response to 10(-5) M norepinephrine, and vasodilation in response to acetylcholine were also not altered in pulmonary vessels taken from control sheep and exposed in vitro to tumor necrosis factor-alpha (400 U/ml). Our results suggest that loss of endothelium-dependent relaxation in pulmonary vessels supports the sustained pulmonary hypertension that develops after prolonged exposure to endotoxin.

Acetylcholine↗
PubMed1997

Endotoxin priming of thromboxane-related vasoconstrictor responses in perfused rabbit lungs.

In prior studies of perfused lungs, endotoxin priming markedly enhanced thromboxane (Tx) generation and Tx-mediated vasoconstriction in response to secondarily applied bacterial exotoxins. The present study addressed this aspect in more detail by employing precursor and intermediates of prostanoid synthesis and performing functional testing of vasoreactivity and measurement of product formation. Rabbit lungs were buffer perfused in the absence or presence of 10 ng/ml endotoxin. Repetitive intravascular bolus applications of free arachidonic acid provoked constant pulmonary arterial pressor responses and constant release reactions of TxA2 and prostaglandin (PG) I2 in nonprimed lungs. Within 60-90 min of endotoxin recirculation, which provoked progressive liberation of tumor necrosis factor-alpha but did not effect any hemodynamic changes by itself, both pressor responses and prostanoid release markedly increased, and both events were fully blocked by cyclooxygenase (Cyclo) inhibition with acetylsalicylic acid (ASA). The unstable intermediate PGG2 provoked moderate pressor responses, again enhanced by preceding endotoxin priming and fully suppressed by ASA. Vasoconstriction also occurred in response to the direct Cyclo product PGH2, again amplified after endotoxin pretreatment, together with markedly enhanced liberation of TxA2 and PGI2. In the presence of ASA, the priming-related increase in pressor responses and the prostanoid formation were blocked, but baseline vasoconstrictor responses corresponding to those in nonprimed lungs were maintained. Pressor responses to the stable Tx analog U-46619 were not significantly increased by endotoxin pretreatment, but some generation of TxA2 and PGI2 was also noted under these conditions. We conclude that endotoxin priming exerts profound effects on the lung vascular prostanoid metabolism, increasing the readiness to react with Tx-mediated vasoconstrictor responses to various stimuli, suggesting that enhanced Cyclo activity is an important underlying event.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Apocynin improves diaphragmatic function after endotoxin administration.

Free radicals are known to play an important role in modulating the development of respiratory muscle dysfunction during sepsis. Moreover, neutrophil numbers increase in the diaphragm after endotoxin administration. Whether or not superoxide derived from infiltrating white blood cells contributes to muscle dysfunction during sepsis is, however, unknown. The purpose of the present study was to examine the effect of apocynin, an inhibitor of the superoxide-generating neutrophil NADPH complex, on endotoxin-induced diaphragmatic dysfunction. We studied groups of rats given saline, endotoxin, apocynin, or both endotoxin and apocynin. Animals were killed 18 h after injection, a portion of the diaphragm was used to assess force generation, and the remaining diaphragm was used for determination of 4-hydroxynonenal (a marker of lipid peroxidation) and nitrotyrosine levels (a marker of free radical-mediated protein modification). We found that endotoxin reduced diaphragm force generation and that apocynin partially prevented this decrease [e.g., force in response to 20 Hz was 23 +/- 1 (SE), 12 +/- 2, 23 +/- 1, and 19 +/- 1 N/cm(2), respectively, for saline, endotoxin, apocynin, and endotoxin/apocynin groups; P < 0.001]. Apocynin also prevented endotoxin-mediated increases in diaphragm 4-hydroxynonenal and nitrotyrosine levels (P < 0.01). These data suggest that neutrophil-derived free radicals contribute to diaphragmatic dysfunction during sepsis.

Acetophenones↗
PubMedDate not supplied

Endotoxin-induced renal failure. II. A role for tubular hypoxic damage.

Endotoxin-induced hypotension and altered renal microcirculation could lead to tubular injury, particularly at the physiologically hypoxic outer medulla. We explored this hypothesis in isolated perfused kidneys and in vivo in rats subjected to endotoxemia. Rat kidneys were removed 15 min after endotoxin injection in vivo (from Escherichia coli 0127:B8, 1 mg/kg i.p.) and perfused with oxygenated medium supplemented with 20 amino acids and endotoxin. Glomerular filtration rate and filtration fraction markedly declined (0.4 +/- 0. 1 ml/min and 1.1 +/- 0.1, respectively) as compared with control kidneys (0.7 +/- 0.1 ml/min and 1.8 +/- 0.1, n = 8-12 per group; p < 0.05). Hypoxic injury to medullary thick ascending limbs in the innermost outer medulla increased (47 +/- 9% of tubules vs. 16 +/- 8% in controls, p < 0.05). When rats were preconditioned with an additional endotoxin injection 16 h earlier (a manipulation that markedly reduces cortical and medullary blood flow), glomerular filtration rate and filtration fraction further declined to 0.1 +/- 0.0 ml/min and 0.4 +/- 0.1, respectively (p < 0.01), and tubular sodium reabsorption fell to 81 +/- 12 vs 98 +/- 0% in controls (p < 0.05). Tubular damage, however, did not increase (20 +/- 7%), probably reflecting a decline in reabsorptive workload and oxygen requirement. In rats subjected to a single or two repeated daily doses of endotoxin (1 mg/kg i.p.) plasma creatinine comparably rose 41% on the average over 24 h, creatinine clearance fell by 27% (p < 0.0001), but tubular damage was absent. By contrast, in rats preconditioned with indomethacin and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (10 mg/kg), the addition of endotoxin markedly augmented outer medullary hypoxic tubular damage both in S(3) segments (27 +/- 10 vs 1 +/- 1%) and in medullary thick ascending limbs (38 +/- 11 vs. 10 +/- 5%, n = 7-8; p < 0.05). It is concluded that under special conditions, such as altered medullary oxygen balance or defective nitric oxide or prostaglandin synthesis, endotoxin may predispose to hypoxic outer medullary tubular damage.

Absorption↗
PubMed1998

Superoxide-mediated glomerulopathy in the endotoxin-treated pregnant rat.

In the present study the role of superoxide in the glomerular damage in the low-dose endotoxin-infused pregnant rats was investigated. On day 14 of pregnancy, 12 rats were infused for 1 h with 1.0 microgram/kg bw endotoxin via a permanent jugular vein cannula. Of these rats, 6 were treated with SOD both prior to endotoxin infusion (7,000 U/kg) and 30 min (7,000 U/kg) and 4 h (14,000 U/kg) after the start of the infusion (SOD rats). The other 6 rats received no SOD treatment (endotoxin rats). Control pregnant rats were infused for 1 h with saline (saline rats; n = 6). Urinary albumin was measured on days 15 and 19 of pregnancy. On day 21, rats were sacrificed and kidney specimens were snap-frozen. Cryostat kidney sections were stained for fibrinogen, ecto-ATP diphosphohydrolase (e-ATPase) activity, polymorphonuclear cells, monocytes and various adhesion molecules on the endothelium and the leukocytes. SOD treatment appeared to significantly prevent the increased urinary albumin excretion and the decrease of glomerular e-ATPase activity which were observed in endotoxin-treated rats. This effect of SOD treatment after endotoxin infusion was associated with a significant inhibition of glomerular monocyte influx and a significant inhibition of adhesion molecule expression (glomerular ICAM-1 and VCAM-1 and leukocyte LFA-1 and VLA-4). The present data suggest that in the endotoxin-infused pregnant rat, production of superoxide in the first few hours after the infusion plays a role in the induction of glomerular damage, leading to albuminuria and diminished e-ATPase expression during the following days.

Adenosine Triphosphatases↗
PubMedDate not supplied

Endotoxin inactivation by enterally applied colostrum of different composition.

BACKGROUND AND PURPOSE: Enteral applied bovine colostrum can significantly reduce endotoxin concentration in plasma. Since colostrum is a mixture of biological active ingredients 3 possible substances which are able to influence the endotoxin elimination were concentrated in 3 different colostrum products. Immunoglobulin-, lactoferrin- and casein-enriched colostra and lactoferrin alone were orally administered to endotoxinaemic rats. METHODS: Endotoxinaemia was induced to rats by enteral application of 10(10) E. coli together with 40 mg Nebacetin. Control animals received albumin. From all rats plasma samples were taken over the time of 5 h and endotoxin concentration determined with limulus lysate and chromogenic substrate. RESULTS: Whereas in control animals as well as in animals treated with casein-enriched colostrum a marked increase of endotoxin values to over 130 EU/dl could be observed after 5 h, the oral application of gammaglobulin-enriched and especially lactoferrin-enriched colostrum decreased endotoxin values by more than 50%. The most effective endotoxin elimination was seen with lactoferrin alone. CONCLUSIONS: From this results it can be concluded that not only gammaglobulin but especially lactoferrin seems to be responsible for the elimination of endotoxin with regard to enterally applied colostrum preparations.

Administration, Oral↗
PubMed2004

Characterization of the DialGuard device for endotoxin removal in hemodialysis.

Bacterial pyrogens, capable of penetrating dialyzer membranes, are responsible for a systemic inflammatory reaction in hemodialysis patients. Dialyzer reuse, involving rinsing of the dialyzer with pyrogen-containing water, may exacerbate this situation. Studies of the mechanism of action of endotoxin suggest that it irreversibly damages the vascular endothelium. The novel endotoxin removal method described here, is based on affinity-binding of endotoxin by the adsorbent ClarEtox, a USP Class VI-certified resin that is the active component of the medical device DialGuard. Under standard hemodialysis operating conditions, challenge of DialGuard with Pseudomonas maltophilia supernatant-spiked dialysate, containing 35-193 EU/ml endotoxin, resulted in endotoxin levels below 0.05 EU/ml in the treated dialysate. DialGuard was able to decrease endotoxin concentrations in the dialysate from a range of 2.39-8.49 to <0.005 EU/ml. DialGuard supports high fluid velocities at low back pressures and can be sanitized using the heat sanitization cycle of hemodialysis machines. DialGuard offers a simple, user-friendly way to reduce the concentration of endotoxin in dialysate and water for dialysis at a low cost.

Chromatography, Affinity↗
PubMed1987

Measurement of operative plasma endotoxin levels in jaundiced and non-jaundiced patients.

A study of portal plasma endotoxin levels was performed using a chromogenic limulus amoebocyte lysate (LAL) assay. The assay proved sensitive and reproducible. In only 1 of 25 healthy subjects was the systemic plasma endotoxin level above 100 pg/ml (equivalent Escherichia coli 0111B4). In 30 non-jaundiced patients undergoing surgery the mean (+SEM) portal plasma endotoxin level (60 + 9 pg/ml) was significantly higher (p less than 0.05) than the mean level in the systemic blood (46 + 6 pg/ml), supporting the concept of endotoxin absorption from the intestine into the portal blood. In 20 patients with obstructive jaundice undergoing surgery 42% of portal, 45% of inferior mesenteric and 35% of systemic venous plasma endotoxin levels were above 100 pg/ml. There were significantly higher levels in the portal (p less than 0.05) and inferior mesenteric (p less than 0.05) compared with the systemic blood. Neither the presence of malignancy nor the duration of surgery appeared to influence endotoxin absorption. The significance of raised plasma endotoxin levels in obstructive jaundice is discussed.

Adult↗
PubMed1994

Is endotoxin-induced hypotension related to nitric oxide formation?

Nitric oxide (NO), an endothelium-derived relaxing factor (EDRF), is released by different types of cells under the influence of endotoxin and various cytokines: a causative role of endothelium-derived NO in the endotoxin-induced hypotension has thus been suggested. To test the hypothesis that NO may be involved in the acute hypotension following endotoxin challenge, we administered a competitive inhibitor of NO synthase, L-N-monomethylarginine (L-NMMA) to anesthetized dogs in the presence and absence of endotoxin. Dogs were randomly allocated to three groups. Group 1 (n = 3) was given Escherichia coli endotoxin (3 mg/kg, i.v.), group 2 (n = 3) was given L-NMMA (5 mg/kg, i.v. bolus) 15 min after endotoxin and group 3 (n = 3) was given L-NMMA only. One additional dog was given L-arginine (100 mg/kg, i.v. bolus) after L-NMMA and endotoxin to reverse the inhibition of NO synthase. In each animal, saline was infused intravenously throughout the experiment to restore and maintain pulmonary artery occluded pressure at baseline level. After L-NMMA, the increases in mean arterial pressure were similar in group 2 (from 55 +/- 18 to 75 +/- 15 mm Hg, p < 0.01) and in group 3 (from 107 +/- 27 to 128 +/- 24 mm Hg, p < 0.01). Systemic vascular resistance increased from 2,994 +/- 72 to 3,658 +/- 673 dyn.s.cm-5 (p < 0.01) in group 3. Group 1 had lower plasma lactate levels than group 2 (3.5 +/- 2.3 +/- vs. 2.0 +/- 1.6 mEq/l, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1996

Determination of endotoxin-neutralizing capacity of plasma in postsurgical patients.

In 92 patients who underwent abdominal and goiter surgery endotoxin and endotoxin-neutralizing capacity (ENC) were determined in plasma preoperatively and daily postoperatively. Endotoxin plasma levels started to increase on day 1 in patients who were laparotomized. Correspondingly ENC was reduced during the 1st postoperative week. Even on the 1st postoperative day determination of ENC made the differentiation between patients possible who showed an uneventful course and patients who developed pneumonia, pulmonary failure, or mental disorders. Furthermore the need for diuretics in order to maintain sufficient renal function was associated with lower ENC during days 1-3. Endotoxin plasma levels were significantly elevated in patients who developed pneumonia during days 1-4, whereas the occurrence of pulmonary failure was only correlated with elevated endotoxin levels on day 3. Endotoxemia was pronounced in patients needing diuretics on days 1, 4, and 5. In patients who underwent goiter surgery ENC changed significantly as found for endotoxin plasma values during the postoperative course. Determination of endotoxin and especially ENC with the use of the limulus amebocyte lysate test turned out to be a reliable method correlating with impending complications at least in postsurgical patients.

Adult↗
PubMed1988

Endotoxin-induced auto-immunity in mice. II. Reactivity of LPS-hyporesponsive and C5-deficient animals.

Auto-antibody responses and circulating immune complex levels of mice with abnormal reactions to endotoxin were investigated after injection with the bacterial product. It was observed that C3H/HeJ mice displayed very high background plaque-forming cell responses towards bromelain-treated isologous erythrocytes which were slightly enhanced by endotoxin treatment. The same animals, however, did not bear autohaemolysins in their serum, but became so upon endotoxin injection. A possible relationship between the high background reactivity of C3H/HeJ mice and the low toxicity of endotoxin in these animals is discussed. Neither untreated nor lipopolysaccharide-injected C3H/HeJ mice showed significant immune complex levels in their sera. This may be explained by their hyporesponsiveness, but by a low sensitivity to the toxic effects of endotoxin as well. C5-deficient and C5-sufficient mice showed similar auto-immune reactions, indicating that C5a, which is responsible for other effects of endotoxin, is not involved in endotoxin-induced auto-immunity.

Animals↗
PubMed1993

Age-related changes in endotoxin sensitivity and the febrile response of newborn rabbits.

Thermoregulatory responses to pyrogens in the immediate newborn period have been reported suppressed or undeveloped. In this study we investigated these responses in the newborn rabbit. Endotoxin (Escherichia coli LPS) was injected intraperitoneally in rabbits at different doses on day 0 (day of delivery), 1 or 3 of life, each animal being used only once. Oxygen consumption (VO2) and colonic temperature (Tc) were measured continuously for up to 5 h following endotoxin administration. On all days, a thermogenic response of a similar pattern was seen. At a low dose of endotoxin, there was a monophasic rise in VO2 that reached a peak at 2 h, followed by a plateau phase lasting a further 2-3 h. At an intermediate dose the response was biphasic with an initial smaller peak after 45-60 min and a second more sustained peak developing by about 2 h. At a higher dose the depression between the two peaks became deeper and longer with the second peak becoming more delayed and weaker. As animals got older, the doses needed to produce this sequence increased. On day 0 the increased VO2 caused by endotoxin was not accompanied by an increase in Tc. By day 3, Tc rose with the increase in VO2. We conclude that rabbits on the day of delivery respond to endotoxin with an increase in VO2 and by day 3 this is accompanied by an increase in Tc. The pattern of VO2, changes from monophasic to biphasic with increasing doses of endotoxin and the sensitivity to endotoxin decreases over the first 3 days of life.

Age Factors↗
PubMed2006

Antithrombin reduces endotoxin-induced hypotension by enhancing pulmonary sensory neuron activation in rats.

We recently demonstrated that activation of the pulmonary sensory neurons plays a critical role in prevention of endotoxin-induced shock by releasing calcitonin gene-related peptide (CGRP) in rats. CGRP increased the endothelial production of prostacyclin (PGI(2)) in the lungs, thereby preventing endotoxin-induced shock response by inhibiting tumor necrosis factor-alpha (TNF-alpha) production. Since antithrombin (AT) enhances sensory neuron activation, we hypothesized that AT might reduce endotoxin-induced hypotension by enhancing the activation of pulmonary sensory neurons in rats. We examined this possibility using a rat model of endotoxin shock. AT-induced effects including reduction of hypotension (n = 5) and inhibition of induction of iNOS (n = 4 or 5) and TNF- alpha (n = 5) in the lungs of endotoxin-treated animals were completely reversed by pretreatment with capsazepine (CPZ) (n = 4 or 5), a vanilloid receptor antagonist, or CGRP(8-37), a CGRP receptor antagonist (n = 4 or 5). AT enhanced endotoxin-induced increases in lung tissue levels of CGRP (n = 4), but this effect of AT was not seen in animals pretreated with CPZ (n = 4). CGRP produced therapeutic effects (n = 5) similar to those induced by AT, and such therapeutic effects were completely abrogated by pretreatment with indomethacin (n = 4). AT increased CGRP release from cultured dorsal root ganglion neurons only in the presence of anandamide (n = 5), and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (n = 5). AT markedly increased intracellular levels of cAMP in the presence of anandamide (n = 5). These results strongly suggested that AT might reduce endotoxin-induced hypotension in rats by enhancing activation of sensory neurons via activation of protein kinase A.

Animals↗
PubMed2004

Potential role of endotoxin as a proinflammatory mediator of atherosclerosis.

Atherosclerosis is increasingly recognized as a chronic inflammatory disease. Although a variety of inflammatory markers (ie, C-reactive protein) have been associated with atherosclerosis and its consequences, it is important to identify principal mediators of the inflammatory responses. One potentially important source of vascular inflammation in atherosclerosis is bacterial endotoxin. Mutations in Toll-like receptor 4 (TLR-4), an integral component of the endotoxin signaling complex, are fairly common in the Caucasian population and have recently been associated with reduced incidence of atherosclerosis and other cardiovascular diseases in some studies. Moreover, epidemiological studies suggest that endotoxemia at levels as low as 50 pg/mL constitutes a strong risk factor for the development of atherosclerosis. Endotoxin concentrations in this range may be produced by a variety of common subclinical Gram-negative infections. In this article, we outline the main elements of the endotoxin signaling receptor complex that initiates proinflammatory signaling (lipopolysaccharide binding protein [LBP], CD14, TLR-4, and MD-2) and discuss how changes in expression of these molecules may affect proatherogenic responses in the vessel wall. We also describe some of the proinflammatory effects of endotoxin that may be relevant to atherosclerosis, and discuss how serum lipoproteins, especially high-density lipoprotein, may modulate endotoxin-induced inflammatory responses. Further, we discuss recent findings suggesting that the lipid-lowering statins may have an additional protective role in blocking at least some of these proinflammatory signaling pathways. Finally, we discuss species diversity with regard to endotoxin signaling that should be considered when extrapolating experimental data from animal models to humans.

Animals↗