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PubMed2003

Increased IP-10 and MIG expression after intra-amniotic endotoxin in preterm lamb lung.

Subtraction hybridization was performed to explore changes in gene expression in the fetal lung after 20 mg of intra-amniotic (IA) endotoxin. Interferon-gamma-inducible 10-kd protein (IP-10) and monokine induced by interferon-gamma (MIG) constituted 20% of 102 endotoxin-induced clones identified in the preterm lamb lung. IP-10 (CXCL10) and MIG (CXCL9) are T-cell chemoattractants that have angiostatic properties. Both IP-10 and MIG mRNA were induced 30- to 40-fold in the fetal lung at 1 to 2 days after IA endotoxin. Intense IP-10 mRNA expression was detected by in situ hybridization in the bronchiolar and peribronchiolar areas and the vascular endothelium after IA endotoxin at all time points tested. MIG mRNA expression was detected initially focally in infiltrating neutrophils (15 hours after IA endotoxin) and later in the bronchiolar and peribronchiolar areas and vascular endothelium (1 day after IA endotoxin). In contrast to endotoxin, IA tumor necrosis factor-alpha or interleukin-1 alpha did not induce IP-10 or MIG mRNA in the lung. IA endotoxin also caused a modest induction of IP-10 and MIG mRNA in the jejunum, liver, and spleen. The IP-10 and MIG receptor CXCR3 was detected in the bronchiolar epithelium of preterm lambs by immunostaining. IP-10 and MIG are potent angiostatic chemokines that may contribute to lung injury and altered pulmonary vascular development in the preterm exposed to chorioamnionitis.

Amnion↗
PubMed1994

Effect of inhaled endotoxin on intraepithelial mucosubstances in F344 rat nasal and tracheobronchial airways.

Increased sputum production and chronic bronchitis are associated with occupational exposure to endotoxin-contaminated organic ducts. The present study examined whether repeated exposure to occupationally relevant concentrations of airborne endotoxin in the F344 rat can alter the volume density of stored intraepithelial mucosubstances (Vs) in the respiratory tract. Rats were exposed to saline or endotoxin aerosols for 3 h/day for 3 days and were killed 24 h after the last exposure. Quantitative histochemistry of Vs in airway epithelium was examined at three distinct levels of the respiratory tract (nose, trachea, and lung). Exposure to endotoxin produced a dose-dependent increase in Vs in the intrapulmonary airways. The quantity of Vs in the intrapulmonary airways was significantly increased in animals exposed to as little as 0.3 micrograms/m3 endotoxin. Significant increases in Vs were observed in the trachea only after exposure to > or = 3.1 micrograms/m3 endotoxin, whereas no significant changes were observed in the nasal airways even at concentrations as high as 52.4 micrograms/m3. These results are consistent with earlier findings in which repeated instillation of endotoxin produced significant increases in Vs in the epithelial lining of the pulmonary airways and demonstrate that inhaled endotoxin may play a role in the increase in sputum and chronic bronchitis reported for workers exposed to organic dusts.

Animals↗
PubMed1981

Role of thromboxane and prostacyclin in pulmonary vasomotor changes after endotoxin in dogs.

Cyclooxygenase inhibitors prevent the pulmonary vasomotor changes in response to low-dose endotoxin. We, therefore, explored the role of two highly vasoactive prostanoids, thromboxane A(2), a vasoconstrictor, and prostacyclin, a vasodilator, in the transient pulmonary vasoconstriction and subsequent loss of alveolar hypoxis vasoconstriction (AHPV) that follows endotoxin. AHPV was tested in the dog with a double-lumened endotracheal tube allowing ventilation of one lung with nitrogen as a hypoxic challenge while the other lung was ventilated with oxygen to maintain systemic oxygenation. Relative distribution of perfusion to the two lungs was assessed with intravenous (133)Xe and external scintillation detectors. The stable metabolites of thromboxane and prostacyclin, i.e., thromboxane B(2) and 6-keto-prostaglandin F(1alpha) were measured in plasma with radioimmunoassay. 15 mug/kg i.v. of endotoxin induced no rise in pulmonary vascular resistance (PVR), but prevented AHPV so that the initial 33% (+/-2 SEM) decrease in perfusion to the hypoxic lung became only a 2% (+/-1) decrease. Circulating levels of thromboxane and prostacyclin concurrently rose (P < 0.01) from nondetectable levels to 380 pg/ml (+/-40) and 360 pg/ml (+/-130). 150 mug/kg of endotoxin induced a transient rise in PVR from 4.09 to 9.00 mm Hg/liter per min in association (r = 0.89, P < 0.01) with a sharp rise in thromboxane levels to 4,460 pg/ml (+/-1,350) whereas prostacyclin levels were elevated less markedly to 550 pg/ml (+/-400). Prostaglandin F(2alpha), another vasoconstrictor, was not elevated. 30 min after endotoxin when PVR was again base line and AHPV lost, thromboxane fell significantly (P < 0.01) to 2,200 pg/ml (+/-1,100) whereas prostacyclin remained elevated at 360 pg/ml (+/-135), a level similar to that seen when 15 mug/kg of endotoxin induced loss of AHPV. Indomethacin prevented the rise in thromboxane and prostacyclin after endotoxin as well as the changes in pulmonary vasomotor tone. Thus, a complex interaction between thromboxane and prostacyclin is involved in the pulmonary vasomotor response to low-dose endotoxin.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Human very low density lipoproteins and chylomicrons can protect against endotoxin-induced death in mice.

Endotoxemia stimulates many physiologic responses including disturbances in lipid metabolism. We hypothesized that this lipemia may be part of a defensive mechanism by which the body combats the toxic effects of circulating endotoxin. We tested the effects of mixtures of endotoxin, lipoproteins, and lipoprotein-free plasma and determined the ability of varying concentrations of human very low density lipoproteins (VLDL) and chylomicrons, as well as low density lipoproteins (LDL) and high density lipoproteins (HDL), and of the synthetic lipid emulsion SOYACAL to prevent endotoxin-induced death in mice. This study demonstrates that the triglyceride-rich VLDL and chylomicrons, as well as cholesterol-rich LDL and HDL, and cholesterol-free SOYACAL can protect against endotoxin-induced death. Protection required small amounts of lipoprotein-free plasma, and depended on the incubation time and the concentration of lipoprotein lipid. Despite stringent techniques to prevent exogenous endotoxin contamination eight of ten duplicate VLDL preparations contained endotoxin (5,755 +/- 3,514 ng endotoxin/mg triglyceride, mean +/- SEM) making the isolation of endotoxin-free VLDL difficult. In contrast, simultaneous preparations of LDL and HDL were relatively free of endotoxin contamination (3 +/- 3 and 320 +/- 319 ng/mg total cholesterol, respectively), suggesting that the contamination of VLDL occurs in vivo and not during the isolation procedure. These observations suggest a possible role for increased triglyceride-rich lipoproteins in the host's defense against endotoxemia and infection.

Animals↗
PubMed1993

Tolerance to endotoxin-induced expression of the interleukin-1 beta gene in blood neutrophils of humans with the sepsis syndrome.

The induction of genes of host cells stimulated by microbial products such as endotoxin and the tolerance of cells to endotoxin excitation play critical roles in the pathogenesis of microbial-induced acute disseminated inflammation with multiorgan failure (the sepsis syndrome). One gene that is induced in phagocytic cells by endotoxin and that appears to play an essential role in the pathogenesis of the sepsis syndrome is IL-1 beta. We report here that blood neutrophils (PMN) of patients with the sepsis syndrome (sepsis PMN) are consistently tolerant to endotoxin-induced expression of the IL-1 beta gene, as determined by decreased synthesis of the IL-1 beta protein and reductions in IL-1 beta mRNA. This down-regulation of the IL-1 beta gene in sepsis PMN occurs concomitant with an upregulation in the constitutive expression of the type 2 IL-1 receptor (IL-1R2). These phenotypic changes do not persist in PMN of patients recovering from the sepsis syndrome. Tolerance has stimulus and response specificity since sepsis PMN tolerant to endotoxin can respond normally to Staphylococcus aureus stimulation of IL-1 beta production and they normally secrete elastase. Uninfected patients with severe trauma or shock from causes are not tolerant to endotoxin and tolerance is not limited to patients infected with Gram-negative bacteria. The mechanism responsible for tolerance involves pretranslational events and is not due to loss of the CD14 surface protein, a receptor required for endotoxin induction of IL-1 beta in PMN. The physiological significance of the tolerance to endotoxin and increased expression of IL-1R2 on sepsis PMN is unknown, but may represent an attempt by the host to protect itself from the deleterious effects of disseminated inflammation.

Adult↗
PubMedDate not supplied

Effect of superoxide dismutase on endothelium-dependent relaxation of aorta from endotoxin-treated rabbits.

To assess the protective effect of superoxide dismutase (SOD) on the endothelium of aorta in endotoxaemia, we investigated the production of endothelium-derived relaxing factor in aorta obtained from endotoxin-treated rabbits concomitantly receiving SOD or not. Thirty-two male Japanese white rabbits were randomly divided into four groups (n = 8 for each group): one group receiving saline as a placebo, a second receiving 5 mg/kg endotoxin intravenously, a third receiving 5 mg/kg endotoxin intravenously plus SOD, and a fourth receiving SOD alone. SOD was injected intravenously at a dose of 10,000 U/kg before the endotoxin and was infused continuously at a rate of 15,000 units/kg/h throughout the experiment. The tension of the aorta was recorded in vitro 6 h after the start of in vivo treatment with endotoxin or saline. In the aorta of rabbits receiving endotoxin alone, acetylcholine-induced relaxation was reduced by 50%. The SOD fully restored the reduction of acetylcholine-induced relaxation by endotoxin. Histological studies using photomicroscopy revealed endothelial damage in the endotoxin-treated aorta, which was attenuated in the SOD-treated group. These data suggest that intravenous SOD may be an effective treatment for unstable haemodynamics in endotoxaemia.

Acetylcholine↗
PubMed2005

New generation ceramic membranes have the potential of removing endotoxins from dialysis water and dialysate.

Poor water properties, use of concentrated bicarbonate, and biofilm growth in pipes and storage tanks often cause dialysis water and dialysate contamination with bacteria and endotoxins. High-flux dialysis with bicarbonate may favor endotoxin transfer from the dialysate into the blood exposing patients to serious short-and long-term side effects. Ultrafiltration across hydrophobic synthetic membranes effectively removes endotoxins from dialysis water by combined filtration and adsorption. However, repeated sterilization worsens the membrane separation properties,and limits their use. Ceramic membranes are generally more resistant to harsh operating conditions than polymeric membranes, and may represent an alternative for endotoxin removal. Previously, we proved that the ceramic membranes commercially available at that time were not retentive enough to ensure production of endotoxin-free dialysis water. In this paper, we investigated the endotoxin removal capacity of new generation commercial ceramic membranes with nominal molecular weight cut-off down to 1,000. In dead-end filtration, all investigated membranes produced water meeting, the European standards, or close to,when challenged with low endotoxin concentrations, but only one membrane type succeeded at high endotoxin concentrations. In cross-flow filtration, none produced water meeting the European standard. Moreover, sterilization and rinsing procedures altered the separation properties of two out of three membrane types.

Ceramics↗
PubMed2002

Endotoxin in the environment--exposure and effects.

This review deals with endotoxin in the environment and its relation to disease among exposed persons. Data are presented on levels of endotoxin in different environments with maximum values of several microg/m(3). The cellular reactions of importance for inhalation exposure effects are attachment to lipopolysaccharide binding protein, CD14 cell surface protein and TLR-4 receptors. The internalisation of endotoxin in macrophages and endothelial cells results in local production of inflammatory cytokines with subsequent migration of inflammatory cells into the lung and the penetration of cytokines into the blood. These events orchestrate clinical effects in terms of toxic pneumonitis, airways' inflammation and systemic symptoms. Inhalation challenges with pure endotoxin and field studies confirm the relation between these effects and exposure to dusts containing endotoxin. It is possible that polymorphism in genes determining endotoxin reactivity, particularly TLR-4, influences the risk for disease after environmental exposures. Some data suggest that the inflammation caused by inhaled endotoxin may decrease the risk for atopic sensitisation among children and lung cancer among workers exposed to organic dust. Additional research is needed to clarify the role of other environmental agents that are present in connection with endotoxin, particularly (1-->3)-beta-D-glucan from mold cell walls.

Air Pollutants↗
PubMed2004

Detection of endotoxin in sera from children hospitalized for treatment of diarrhea in Bangladesh.

The level of circulating endotoxin was determined in the sera from children hospitalized for treatment of diarrhea at the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh. A significant level of endotoxin was detected in the sera from 23 (54%) of 42 children. On the other hand, in 32 normal controls, endotoxin was below the limits of detection of the assay. Antibiotic and fluid therapy markedly reduced the level of serum endotoxin and improved the general condition of most patients. Non-survivors (n = 5) had higher levels of circulating endotoxin before treatment than survivors (n = 37), suggesting a significant correlation between the serum endotoxin level before treatment and mortality. Malnutrition did not affect the serum endotoxin level in the patients with diarrhea. It was suggested that infection of Gram-negative bacteria might be involved in a significant number of patients with diarrhea in Bangladesh and that endotoxin might play a pathogenic role in those patients.

Bangladesh↗
PubMed2005

Low-dose endotoxin elicits variability in the inflammatory response in healthy volunteers.

Endotoxin has been implicated as a cause of sepsis, inflammation and organ dysfunction after surgery. Patients differ in their response to endotoxin, and this may account for differences in outcome. The traditional human model of endotoxin challenge (2-4 ng/kg) is not associated with significant inter-individual variability in systemic inflammation and may not be suitable for studying variability in the inflammatory response. We examined whether low-dose regimens of endotoxin cause significant variability in inflammation. Volunteers (n = 30) were randomised in a double-blinded ('double-dummy') study to one of 6 dosing regimens: saline (placebo) or Escherichia coli O:113 endotoxin as a 4 ng/kg bolus (positive control), 0.25 ng/kg (bolus), 0.25 ng/kg (30 min infusion), 0.75 ng/kg (bolus) or 0.75 ng/kg (30 min infusion). Temperature, white cell count, platelet count, C-reactive protein and cytokine changes from baseline were measured. In contrast to subjects receiving placebo, those randomised to 4 ng/kg endotoxin exhibited significant systemic inflammation during the 10-h observation period. The four low-dose regimens elicited variability in most markers of inflammation. We conclude that low-dose endotoxin elicits inter-individual variability in inflammation and could be used to test factors that may affect the human response to endotoxin.

Adolescent↗
PubMed1998

Orientation and presence of epithelium are key to endotoxin-induced neutrophil migration.

The mechanisms by which endotoxins mediate neutrophil transepithelial migration and lung inflammation are unclear. It was hypothesized that both the presence and orientation of epithelial cells are critical to endotoxin-induced neutrophil migration. Neutrophil migration was compared through naked filters and filters with A549 lung epithelial monolayers grown on the upper and lower surface of permeable filters to simulate the apical and basal directional movement of neutrophils, respectively. The endotoxin, Pseudomonas aeruginosa lipopolysaccharide, was placed below the filter, acting as either a basal or an apical stimulus. Endotoxin without serum failed to stimulate neutrophil migration. In the presence of 1% human serum, endotoxin-induced neutrophil migration through naked filters was dose dependent. Endotoxin-induced neutrophil migration across A549 monolayers was minimal when the monolayers were cultured on the upper surface of the filters (basal stimulus). In contrast, neutrophil transepithelial migration was much greater and dependent on both dose and time when the monolayer was cultured on the lower surface of the filter (basal to apical neutrophil directional movement). Furthermore, enhanced neutrophil transepithelial migration was greater with an apical than with a basal stimulus. Endotoxin-induced neutrophil transepithelial migration was markedly inhibited (>95%) by actinomycin D pretreatment of the monolayers, suggesting the necessity for intact protein synthesis capacity of the A549 cells. Thus, both the presence and orientation of airway epithelium are key in supporting endotoxin-mediated lung neutrophilic responses.

Cell Movement↗
PubMed2006

Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis.

Endotoxin tolerance is defined as a reduced responsiveness to a lipopolysaccharide (LPS) challenge following a first encounter with endotoxin. Endotoxin tolerance protects against a lethal challenge of LPS and prevents infection and ischemia-reperfusion damage. Endotoxin tolerance is paralleled by a dramatic reduction of tumor necrosis factor (TNF) production and some other cytokines in response to LPS. Endotoxin tolerance involves the participation of macrophages and mediators, such as glucocorticoids, prostaglandins, IL-10, and transforming growth factor-beta. Endotoxin tolerance is accompanied by the up-regulation of inhibitory molecules that down-regulate the Toll-like receptor (TLR)4-dependent signaling pathway. Cross-tolerance between LPS and other TLR specific ligands, as well as IL-1 and TNF, has been regularly reported. A similar loss of LPS reactivity has been repeatedly reported in circulating leukocytes of septic patients and in patients with non-infectious systemic inflammation response syndrome (SIRS). Studies on cellular signaling within leukocytes from septic and SIRS patients reveal numerous alterations reminiscent of those observed in endotoxin tolerant cells. However, altered responsiveness to LPS of leukocytes from sepsis and SIRS patients is not synonymous with a global down-regulation of cellular reactivity. The term 'cellular reprogramming', which has been proposed to qualify the process of endotoxin tolerance, defines well the immune status of circulating leukocytes in septic and SIRS patients.

Animals↗
PubMed1994

Endotoxin induces glutathione reductase activity in lungs of mice.

Glutathione reductase catalyzes the NADPH-dependent conversion of glutathione disulfide to glutathione and helps protect the lung from injury by reactive oxygen. In animals allowed to breathe nearly 100% oxygen, the activities of other antioxidants in the lung can be induced by treatment with endotoxin, and this induction is associated with increased tolerance to hyperoxia. The purpose of this study was to see whether glutathione reductase activity in the lungs of mice increased with endotoxin treatment alone. We studied 60 FVB mice (20 males and 40 females). Half received endotoxin (500 micrograms/kg) intraperitoneally at time 0 and 24 h, and the controls received an equal volume of saline. At 48 h we killed the mice and removed their lungs. Treatment of mice with endotoxin increased glutathione reductase activity in the lung 55% (0.035 +/- 0.005 to 0.054 +/- 0.010 mumol NADPH reduced/min/mg protein; mean +/- SD; endotoxin different from control, p < 0.001). The increase in activity was the same for male and female mice. We measured the specific protein for glutathione reductase by Western analysis and mRNA for glutathione reductase using a slot-blot analysis and found that both increased roughly 2-fold with endotoxin treatment. This suggests that endotoxin treatment resulted in either increased rate of transcription of glutathione reductase mRNA or increased mRNA stability. We conclude that endotoxin treatment increases glutathione reductase activity in the lung and that this increase in activity may play a role in subsequent protection from hyperoxia.

Animals↗
PubMed2003

Intraamniotic endotoxin increases lung antioxidant enzyme activity in preterm lambs.

Proinflammatory stimulation resulting from intraamniotic endotoxin improves lung function, increases surfactant protein mRNA expression and protein content, increases alveolar and lung saturated phosphatidylcholine pools, and accelerates lung morphometric maturation in fetal sheep. The mechanism for induction of lung maturation does not involve an increase in fetal cortisol. The effect of endotoxin on the maturation of a different lung system, the antioxidant enzyme (AOE) system, has not been examined. Therefore, we hypothesized that intraamniotic endotoxin would produce acceleration of AOE activity in fetal sheep at similar doses and schedule of administration to those producing lung functional and surfactant maturation. In a dose-response study, intraamniotic injections of 1, 4, 20, or 100 mg of Escherichia coli 055:beta5 endotoxin were administered 7 d before preterm delivery of sheep at 125 d gestation. In a study examining time interval of administration before delivery, 20 mg of endotoxin was injected at either 1-, 2-, 4-, 7-, or 15-d intervals before preterm delivery at 125 d. Doses of 1-100 mg of endotoxin produced significant increases in glutathione peroxidase activity; doses of 4-100 mg significantly increased catalase activity, whereas doses of 20-100 mg resulted in significant increases in total superoxide dismutase activity. Glutathione peroxidase activity was elevated within 2 d, whereas superoxide dismutase was increased by 4 d and catalase activity increased by 7 d after endotoxin. No AOE increases were sustained for 15 d. Endotoxin increased fetal lung AOE activity at similar dosing amounts and intervals to those producing maturation of lung function and surfactant. Thus, mechanisms involving proinflammatory stimulation, unrelated to glucocorticoid hormones, can induce maturation of the AOE system of the fetal lung.

Amniotic Fluid↗
PubMed1995

Subdiaphragmatic vagotomy suppresses endotoxin-induced activation of hypothalamic corticotropin-releasing hormone neurons and ACTH secretion.

In order to assess the possibility that endotoxin-induced activation of the hypothalamus-pituitary-adrenal (HPA) axis is mediated by vagal afferents, we studied the effects of transection of the vagal nerves on endotoxin-induced Fos expression in hypothalamic corticotropin-releasing hormone (CRH) neurons and plasma ACTH and corticosterone responses. Groups of rats were subjected to sham surgery, complete subdiaphragmatic vagotomy (SVGX), or selective transection of the hepatic branch (HVGX). Two weeks after surgery, endotoxin or saline was injected i.p. and rats were sacrificed by decapitation two hours later. SVGX blocked or attenuated the ACTH response to 20 and 250 micrograms/kg endotoxin, respectively. HVGX did not suppress the ACTH response to either endotoxin dose. In addition, corticosterone responses were not affected by SVGX or HVGX. The endotoxin-induced Fos expression in CRH neurons was suppressed in SVGX, but not in HVGX animals. These observations lead us to postulate that the CRH and ACTH responses to a low dose of endotoxin are mediated by vagal afferents. The responses to a high dose of endotoxin involve additional neuronal or humoral pathways.

Adrenocorticotropic Hormone↗
PubMed1997

Endotoxin inhibits the reproductive neuroendocrine axis while stimulating adrenal steroids: a simultaneous view from hypophyseal portal and peripheral blood.

This study was designed to test the hypothesis that systemic immune challenge with endotoxin inhibits the reproductive axis centrally by suppressing GnRH pulsatile release into hypophyseal portal blood. Using alert, normally behaving, ovariectomized ewes, we sampled hypophyseal portal blood at 10-min intervals beginning 4 h before and continuing 10 h after endotoxin (400 ng/kg, iv bolus, n = 6) or saline (vehicle, iv, n = 6). Simultaneous jugular samples for measurement of LH, cortisol, and progesterone were taken, and core body temperature was monitored by telemetry. Saline had no effect on any of the parameters in control ewes. In contrast, endotoxin dramatically inhibited the reproductive neuroendocrine axis coincident with stimulating the adrenal steroids, cortisol and progesterone, and elevating body temperature. Mean GnRH collection rate and GnRH pulse amplitude were suppressed (pre- vs. 7 h postendotoxin: collection rate 0.93 +/- 0.31 vs. 0.34 +/- 0.13 pg/min; amplitude 4.13 +/- 1.33 vs. 1.30 +/- 0.41 pg/min per pulse; P < 0.05 and P = 0.01). However, endotoxin did not have a significant effect on GnRH pulse frequency. Along with inhibited GnRH secretion, endotoxin significantly suppressed mean LH concentrations (P = 0.001) and LH pulse amplitude (P < 0.05). In addition, endotoxin suppressed LH pulse frequency (P = 0.01). Coincident with reproductive inhibition, endotoxin stimulated cortisol (P < 0.001), progesterone (P < 0.01), and core body temperature (P < 0.001). We conclude that the suppressive effects of endotoxin on the reproductive axis can be mediated centrally through an inhibition of GnRH and thus LH pulsatile secretion. The coincident stimulation of cortisol, progesterone, and temperature raises the possibility that the central inhibition of the reproductive system may be a consequence of any or all of these activated parameters.

Animals↗
PubMed1998

Endotoxin injection increases growth hormone and somatostatin secretion in sheep.

Endotoxin has been shown to stimulate GH secretion in human and sheep. However, changes in hypothalamic neurohormones involved in the GH regulation by endotoxin have never been studied in vivo. In sheep it is possible to collect hypophysial portal blood (HPB) and quantify GH-releasing hormone (GHRH) and somatostatin (SRIH) secretion under physiological conditions. The purpose of this study was to determine the effect of an acute i.v. endotoxin administration on the secretion of these peptides in sheep. Endotoxin induced a sustained increase of GH (x6.2 +/- 1.3) in intact rams. This stimulation was delayed and less marked when compared with the hypothalamic-pituitary-adrenal axis. Surprisingly, the GH increase was associated with an important rise of jugular (x10.6 +/- 2.4) and portal (x7.9 +/- 3) SRIH levels, without a significant GHRH increase. To determine if the portal SRIH increase was a consequence of an increased short feedback of GH, we studied GH response to endotoxin after a previous GHRH injection to deplete the pituitary pools of GH. In that case, despite the absence of increase of GH after endotoxin treatment, SRIH levels was markedly increased. For the first time we have observed an experimental situation in sheep with a simultaneous and closed amplitude increase in jugular and portal SRIH. The source of jugular SRIH is likely the gastrointestinal tract and the increased jugular SRIH release in systemic circulation might be in part responsible for the increase of hypophysial portal SRIH. Ultimately our results show that endotoxin induced a complex reaction at multiple levels with a specific increase in both portal and peripheral SRIH levels. The surprising association of a lack of change in GHRH release and an increased secretion of SRIH with the increase of GH suggests that the effect of endotoxin on GH axis is mainly a pituitary one. The selective blockade of somatostatin should be useful for a better knowledge of the role of SRIH stimulation in the physiopathology of septic shock.

Adrenocorticotropic Hormone↗
PubMed2000

Prostaglandins mediate the endotoxin-induced suppression of pulsatile gonadotropin-releasing hormone and luteinizing hormone secretion in the ewe.

Five experiments were conducted to test the hypothesis that PGs mediate the endotoxin-induced inhibition of pulsatile GnRH and LH secretion in the ewe. Our approach was to test whether the PG synthesis inhibitor, flurbiprofen, could reverse the inhibitory effects of endotoxin on pulsatile LH and GnRH secretion in ovariectomized ewes. Exp 1-4 were cross-over experiments in which ewes received either flurbiprofen or vehicle 2 weeks apart. Jugular blood samples were taken for LH analysis throughout a 9-h experimental period. Depending on the specific purpose of the experiment, flurbiprofen or vehicle was administered after 3.5 h, followed by endotoxin, vehicle, or ovarian steroids (estradiol plus progesterone) at 4 h. In Exp 1, flurbiprofen reversed the endotoxin-induced suppression of mean serum LH concentrations and the elevation of body temperature. In Exp 2, flurbiprofen prevented the endotoxin-induced inhibition of pulsatile LH secretion and stimulation of fever, reduced the stimulation of plasma cortisol and progesterone, but did not affect the rise in circulating tumor necrosis factor-alpha. In Exp 3, flurbiprofen in the absence of endotoxin had no effect on pulsatile LH secretion. In Exp 4, flurbiprofen failed to prevent suppression of pulsatile LH secretion induced by luteal phase levels of the ovarian steroids progesterone and estradiol, which produce a nonimmune suppression of gonadotropin secretion. In Exp 5, flurbiprofen prevented the endotoxin-induced inhibition of pulsatile GnRH release into pituitary portal blood. Our finding that this PG synthesis inhibitor reverses the inhibitory effect of endotoxin leads to the conclusion that PGs mediate the suppressive effects of this immune/inflammatory challenge on pulsatile GnRH and LH secretion.

Animals↗