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PubMed2005

Airborne endotoxin in woodworking (joinery) shops.

Symptoms such as shortness of breath and cough have been noted in woodworking facilities even where wood dust itself is well-controlled. Suspicion has fallen on other possible contaminants in the workplace atmosphere, including bacterial endotoxin. A few studies have indicated potentially high endotoxin exposure with exposure to fresh wood in sawmills and in the production of fiberboard and chipboard, but fewer studies have been carried out on exposure to endotoxin in dry wood work, for example in joineries. A study of the endotoxin content of airborne wood dust samples from US woodworking facilities is presented, from the re-analysis of samples which previously had been taken to establish mass collection relationships between the IOM sampler, the closed-face 37 mm plastic cassette (CFC) sampler and the Button sampler. Endotoxin was strongly correlated with total dust, but the endotoxin content of a few fresh wood samples was found to be up to ten times higher per unit of wood dust than for dried-wood samples, and this difference was significant. No long-term time-weighted average sample exceeded the recommended limit value of 50 EU m(-3) (EU, endotoxin units)used in the Netherlands, although a number of the IOM samples came close (seven samples or 44% exceeded 20 EU m(-3)) and one short-term (48 minute) sample registered a high value of 73 EU m(-3). The geometric mean concentration from the IOM samples (11 EU m(-3)) is within the range of geometric means found from Australian joineries (3.7-60, combined: 24 EU m(-3)). In contrast, the corresponding values from the CFC (3.6 EU m(-3)), and the Button sampler (2.1 EU m(-3)) were much lower and no samples exceeded 20 EU m(-3). Endotoxin is likely only to be a significant problem in working with dried woods when associated with very high dust levels, where the wood dust itself is likely to be a cause for concern. The results from the few samples in this study where fresh wood was being worked were similar to results from other studies involving fresh woods. The agreement between these studies is encouraging given the difficulties of endotoxin analysis and the wide variation often expected between different laboratories.

Air Pollutants, Occupational↗

PubMed2003

Inhaled endotoxin and organic dust particulates have synergistic proinflammatory effects in equine heaves (organic dust-induced asthma).

BACKGROUND: Equine heaves is a naturally occurring organic dust-induced asthma characterized by airway neutrophilia, mucus hypersecretion and obstructive lung dysfunction. However, the relative role of different dust components in disease severity remains unclear. OBJECTIVE: This study investigated the relative contribution of inhaled endotoxin and organic dust particulates (mainly mould spores) in inducing heaves in heaves-susceptible horses. METHODS: Control and heaves-susceptible horses received inhalation challenges with hay dust suspension (HDS) before and after lipopolysaccharide (LPS) depletion. Heaves-susceptible horses also received inhalation challenge with HDS particulates with and without the addition of LPS and were housed in two separate dusty environments during which mould and endotoxin exposure was measured. The airway inflammatory and functional response to each challenge was measured. RESULTS: Depletion of endotoxin from HDS attenuated the airway neutrophilia and abrogated the airway dysfunction induced in heaves horses by inhaled HDS. The airway response was re-established by adding back LPS to the depleted HDS, confirming that the attenuation in airway response was due specifically to endotoxin depletion. Interestingly, the magnitude of alteration in airway response following endotoxin depletion and add-back was greater than that which could be attributed solely to endotoxin per se, indicating that the LPS activity was enhanced by the other dust components. Consistent with this possibility, washed particulates harvested from HDS enhanced the airway response to inhaled LPS in heaves horses. Heaves horses given two different hay/straw challenges had a significantly different severity of airway inflammation and dysfunction, despite airborne dust and endotoxin concentrations in the horses' breathing zones being similar. CONCLUSION: Although inhaled endotoxin appears not to be the only determinant of disease severity in heaves, it does contribute significantly to the induction of airway inflammation and dysfunction. This contribution is largely via the synergistic action of inhaled endotoxin and organic dust particulates, although other soluble dust components also contribute to a lesser degree.

Animals↗

PubMed1997

Regulation of endotoxin-induced IL-6 production in liver sinusoidal endothelial cells and Kupffer cells by IL-10.

Sinusoidal endothelial cells and Kupffer cells are the first cell populations in the liver that come into contact with gut-derived endotoxin in portal blood. Although endotoxin concentrations as high as 1 ng/ml are physiologically present in portal blood, no local inflammation is seen. We show that the proinflammatory cytokine IL-6, which is central to the development of inflammatory reactions in the liver, is produced by sinusoidal endothelial cells and Kupffer cells in response to low concentrations of endotoxin (100 pg/ml to 1 ng/ml). The anti-inflammatory cytokine IL-10 down-regulated endotoxin-induced IL-6 release in endothelial and Kupffer cells. Importantly, Kupffer cells secreted IL-10 after endotoxin stimulation and may therefore participate in the local regulation of inflammation. We have found that IL-6 secretion in Kupffer cells is tightly regulated by endogenous IL-10, because increased IL-6 secretion resulted when neutralizing antibodies to IL- 10 were added to resting and endotoxin-challenged Kupffer cells. Furthermore, repeated exposure of endothelial cells to endotoxin induced a state of tolerance which resulted in decreased release of IL-6 in response to a second endotoxin challenge. Our results support the notion that inflammatory reactions in the liver in response to endotoxin are down-regulated by local release of the anti-inflammatory cytokine IL-10 that is produced by Kupffer cells.

Animals↗

PubMed1999

The role of amoebocytes in endotoxin-mediated coagulation in the innate immunity of Achatina fulica snails.

Achatina amoebocyte lysate (AAL) derived from amoebocytes of Achatina fulica was activated by Gram-negative bacterial endotoxins in a time-dependent manner resulting in gel formation/coagulation. The activation and maximum proliferation of amoebocytes was observed 40 min after intramuscular injection (20 microg/snail) of endotoxin. Endotoxin-mediated proteolytic activity of AAL towards a serine-protease-specific chromogenic substrate was maximum at pH 8.0, 37 degrees C and within 15 min in a divalent-cation-dependent manner. The AAL activity induced by the endotoxin was directly dependent on the endotoxin concentration, showed a high specificity and saturated at higher endotoxin concentrations. An endotoxin-sensitive factor (ESF) was purified from AAL to apparent homogeneity by single-step affinity chromatography on a heparin-Sepharose 4B column. Native ESF of molecular weight 140 000 was composed of two identical subunits of molecular weight 70 000 attached through non-covalent association. A strong binding to endotoxin (Escherichia coli 055:B5) was exhibited by ESF with a 40-fold higher biological activity than AAL. The ESF was shown to have a unique Phe-Ile active site with regard to its alternate activation by alpha-chymotrypsin instead of endotoxin. The ESF was characterized as a serine protease type as evidenced by potent inhibition with specific inhibitors.

Animals↗

PubMed2000

Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages.

Cyclooxygenase-2 (COX-2), the enzyme primarily responsible for induced prostaglandin synthesis, is an immediate early gene induced by endotoxin in macrophages. We investigated the cis-acting elements of the COX-2 5'-flanking sequence, the transcription factors and signaling pathways responsible for transcriptional activation of the COX-2 gene in endotoxin-treated murine RAW 264.7 macrophages. Luciferase reporter constructs with alterations in presumptive cis-acting transcriptional regulatory elements demonstrate that the cyclic AMP-response element and two nuclear factor interleukin-6 (CCAAT/enhancer-binding protein (C/EBP)) sites of the COX-2 promoter are required for optimal endotoxin-dependent induction. In contrast, the E-box and NF-kappaB sites are not required for endotoxin-dependent induction. Inhibition of endotoxin-induced NF-kappaB activation by expression of an inhibitor-kappaB alpha mutant does not block endotoxin-dependent COX-2 reporter activity. Overexpression of c-Jun, C/EBPbeta, and C/EBPdelta enhances induction of the COX-2 reporter, while overexpression of cyclic AMP-response element-binding protein or "dominant negative" C/EBPbeta represses COX-2 induction. In addition, endotoxin rapidly and transiently elicits c-Jun phosphorylation in RAW 264.7 macrophages. Cotransfection of the COX-2 reporter with dominant negative expression vectors shows that endotoxin-induced COX-2 gene expression requires signaling through a Ras-independent pathway involving the adapter protein ECSIT and the signaling kinases MEKK1 and JNK. In contrast, endotoxin-induced COX-2 reporter activity is not blocked by overexpression of dominant-negative forms of Raf-1, ERK1, or ERK2.

Adaptor Proteins, Signal Transducing↗

PubMed2004

The measurement and health impact of endotoxin contamination in organic dusts from multiple sources: focus on the cotton industry.

Endotoxin is derived from Gram-negative bacterial membranes, and its inflammatory effects following inhalation are well characterized. The significance of this fact becomes apparent when the wide-ranging environments containing high levels of this microbial product are considered. Endotoxin is present in numerous industrial environments, especially where organic fibers are processed. Microbial contamination of these fibers mainly occurs at the agricultural stage. Materials such as flax and hemp are affected in this way, but the most important product in this context is cotton, from which chronic dust inhalation causes the disease byssinosis. Despite the fact that endotoxin constitutes a significant threat to public health, there are currently no occupational exposure limits for this toxicant. This communication describes the toxicology of endotoxin, and its role in inhalation-induced disease, focusing on measurement of airborne endotoxin in the occupational and domestic environments using the Limulus amebocyte lysate (LAL) enzyme assay. Following the success of the LAL assay for measuring endotoxin in dusts, our laboratory has examined its application to aqueous washes from cotton fibers. Reproducibility of the results was high, and data are presented displaying levels of endotoxin contamination in fibers from different cotton producing countries. Hence, worldwide comparison of industrial endotoxin concentrations can be readily made using this test. It would be highly desirable if the performance of the LAL assay facilitated introduction of industrial endotoxin safety limits, and in spite of minor surmountable shortcomings, the test is accurate, reliable, and well field-tested, so its continued widespread use may achieve this goal.

Air Pollutants, Occupational↗

PubMed1961

The susceptibility of mice to bacterial endotoxins.

Albino mice (Rockefeller NCS strain) raised and maintained free of ordinary bacterial pathogens, as well as of intestinal Escherichia coli and of Proteus bacilli, were found to be highly resistant to the lethal effect of bacterial endotoxins. When newborn mice of this NCS colony were nursed by foster mothers from another colony raised under ordinary conditions (SS colony from which the NCS colony was derived), they acquired the intestinal flora of the latter animals and became susceptible to the lethal effects of endotoxins. NCS adult mice could be rendered susceptible to the lethal effect of endotoxins by vaccination with heat killed Gram-negative bacilli. The susceptibility thus induced exhibited a certain degree of specificity for the bacterial strain used in vaccination. Although untreated NCS mice were resistant to the lethal effect of endotoxins, they proved exquisitively susceptible to the infection-enhancing effect of these materials. For example, 1 microg. or less of endotoxin was found sufficient to help establish a rapidly fatal septicemia with Staphylococcus aureus. Small amounts of endotoxin (1 microg. or less), administered alone, caused a marked but transient loss of weight. Vaccination with heat-killed Gram-negative bacilli or with killed BCG increased the resistance of NCS mice to the infection-enhancing effect of small amounts of endotoxin. This protective effect exhibited a certain degree of specificity for the bacterial strain from which the toxin used in the infection-enhancing test was derived. These various findings can be explained by assuming that the pathological effects of endotoxins involve at least two unrelated mechanisms; (a) a primary toxicity illustrated in this study by the loss of weight and enhancement of infection resulting from the injection of small doses of toxin; (b) an immunological reaction with lethal consequences which became manifest only in animals sensitized to the endotoxin by prior exposure to Gram-negative bacilli.

Animals↗

PubMed1961

Involvement of adrenergic factors in the effects of bacterial endotoxin.

The possible involvement of adrenergic mechanisms in the effects of Escherichia coli endotoxin was investigated in several preparations. Appropriate pretreatment of rabbits with E. coli endotoxin significantly increased pressor responses to epinephrine and norepinephrine as compared to untreated controls. Exposure of isolated rabbit aorta strips to E. coli endotoxin in a medium containing whole blood or cellular constituents of blood significantly increased the response to epinephrine. Endotoxin had no effect on responses to epinephrine in ritro when plain Krebs-Ringer solution was used. Pretreatment with reserpine or phenoxybenzamine (dibenzyline) protected rabbits and mice against the acute lethal effects of E. coli endotoxin. The time period intervening between reserpine or dibenzyline administration and challenge by endotoxin precluded a direct antiendotoxic action of these agents. In addition, incubation of dibenzyline with endotoxin in vitro, under conditions which would favor reaction, did not decrease the toxicity of the latter. These results indicate that peripheral adrenergic mechanisms are intimately involved in the effects of E. coli endotoxin and support the concept that deleterious effects of endotoxin in shock probably are due to exaggeration of existing vasoconstriction in an already compromised organism.

Adrenergic Agents↗

PubMed1981

Studies of endotoxin-induced decrease in lipoprotein lipase activity.

A variety of invasive stimuli have been shown to induce hyperlipidemia due to impaired removal of triglyceride from the circulation. The mechanism by which endotoxin induces a deficiency in the activity of the key enzyme of triglyceride metabolism, lipoprotein lipase (LPL), has been studied. In C3H/HeN (endotoxin-sensitive) mice, LPL activity in adipose tissue was markedly suppressed 16 h after endotoxin administration. In contrast, the endotoxin-resistant C3H/HeJ mice were less sensitive to the suppressive effect of endotoxin on LPL activity. After endotoxin administration, a transferable factor had been detected in the blood of C3H/HeN mice 2 h after the injection of endotoxin that causes a suppression of adipose tissue LPL activity in C3H/HeJ mice as well as in C3H/HeN mice. Conditioned medium from the cultures of peritoneal exudate cells of C3H/HeN mice incubated in endotoxin also suppresses adipose tissue LPL in C3H/HeJ mice. These studies demonstrate that exudate cells produce a humoral factor in response to endotoxin, which suppresses adipose tissue LPL.

Adipose Tissue↗

PubMed1991

Hydrazine sulfate protects D-galactosamine-sensitized mice against endotoxin and tumor necrosis factor/cachectin lethality: evidence of a role for the pituitary.

In previously published studies, we had demonstrated that hydrazine sulfate pretreatment protected mice against the lethal effects of endotoxin and that this protection was accompanied by a sustained increase in hepatic phosphoenolpyruvate carboxykinase activity (Silverstein, R., C.A. Christoffersen, and D.C. Morrison. 1989. Infect. Immun. 57:2072). The same hydrazine sulfate pretreatment has now been found to protect mice against endotoxin in the D-galactosamine model with an increase in the endotoxin LD50 of approximately four orders of magnitude. Elimination of the pretreatment period, or administration of an additional dose of D-galactosamine at the time of hydrazine sulfate pretreatment, renders the mice refractory to the protection. Given the sensitivity of phosphoenolpyruvate carboxykinase regulation to several hormones, we investigated the possibility that protection may have been hormone mediated. In addition to determining the effect of hydrazine sulfate on the plasma levels of phosphoenolpyruvate carboxykinase regulating hormones, we have investigated the effects of hydrazine sulfate on endotoxin lethality in mice whose capacity to respond hormonally to external stimuli has been compromised by hypophysectomy. Our results show a significant enhancement in circulating levels of plasma corticosterone 30 min after hydrazine sulfate injection. Moreover, hypophysectomy results in a marked increase in sensitivity of mice to endotoxin challenge as well as an abrogation of the protection against endotoxin lethality mediated by hydrazine sulfate. Although hydrazine sulfate protection distinguishes between sensitivity brought on, individually, by D-galactosamine and by hypophysectomy, mice sensitized by both hypophysectomy and D-galactosamine are not protected against endotoxin lethality by hydrazine sulfate. We conclude that hydrazine sulfate protection against endotoxin lethality is endocrine dependent, with the available evidence implicating a pituitary/adrenal axis, with glucocorticoid involvement. In as much as D-galactosamine is known to act directly in the liver in disrupting protein synthesis, it is proposed that events in the liver are critical to the hydrazine sulfate-mediated protection against endotoxin and are possibly the target of the endocrine involvement. Hydrazine sulfate pretreatment also protects D-galactosamine-sensitized mice against the lethal effects of injected tumor necrosis factor/cachectin.

Animals↗

PubMed1994

The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ failure.

We investigated whether the third component of complement (C3) is involved in the pathophysiology of endotoxic shock, and if it is involved, whether it plays a protective role or whether it mediates shock and multiple organ failure. In a prospective, controlled investigation, six Brittany spaniels that were homozygous for a genetically determined deficiency of C3 (C3 deficient, < 0.003% of normal serum C3 levels) and six heterozygous littermates (controls, approximately 50% of mean normal serum C3 level) were given 2 mg/kg of reconstituted Escherichia coli 026:B6 acetone powder as a source of endotoxin, intravenously. All animals were given similar fluid and prophylactic antibiotic therapy, and had serial hemodynamic variables obtained. After E. coli endotoxin infusion, C3-deficient animals had higher peak levels of endotoxin and less of a rise in temperature than controls (P < 0.05). During the first 4 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean central venous pressure and mean pulmonary artery pressure than controls (P < 0.02). During the first 48 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean arterial pH, left ventricular ejection fraction, and mean pulmonary capillary wedge pressure, and greater increases in mean arterial lactate, arterial-alveolar O2 gradient, and transaminases (aspartate aminotransferase and alanine aminotransferase) than controls, (all P < 0.05). After E. coli endotoxin infusion, C3-deficient animals compared to controls had significantly less of a decrease in mean C5 levels (P < 0.01), but similar (P = NS) increases in circulating tumor necrosis factor levels, bronchoalveolar lavage neutrophils, and protein, and similar (P = NS) decreases in blood leukocytes and platelets. Two of six C3-deficient animals and two of six controls died. In summary, after intravenous infusion of E. coli endotoxin, canines with C3 deficiency have decreased endotoxin clearance and worse E. coli endotoxin-induced shock and organ damage. Thus, the third component of the complement system plays a beneficial role in the host defense against E. coli endotoxic shock.

Analysis of Variance↗

PubMed2003

Evaluation of five extraction protocols for quantification of endotoxin in metalworking fluid aerosol.

OBJECTIVES: Occupational exposures to endotoxin-contaminated, water-based metalworking fluids (MWFs) are thought to contribute to cases of respiratory illness. Before occupational exposure limits for endotoxin can be proposed, accuracy and reproducibility of laboratory measurements must be established. The method most commonly used to quantify endotoxin is the Limulus amebocyte lysate (LAL) assay and this is the basis for the American Society for Testing and Materials (ASTM) method E2144-01. This study was conducted to generate multiple samples with similar mass and endotoxin loading in order to compare four alternative extraction methods with the ASTM method. METHODS: Using an exposure chamber system that provides a uniform distribution of MWF mist, aerosols with three concentrations of endotoxins (4.5, 350 and 1141 EU/m(3)) were collected simultaneously on multiple filter samples. The filters were examined for endotoxin concentration using five different extraction protocols: extraction with 1 h shaking at 25 degrees C in 30 ml pyrogen-free water (PFW) (protocol 1) or in PFW with 0.05% Tween-20 (protocol 2); or shaking at 68 degrees C in 30 ml PFW (protocol 3) or PFW with Tween-20 (protocol 4); or extraction into 20 ml PFW with sonication at 25 degrees C and pH adjustment to 7.5 (ASTM protocol). RESULTS: The uniformity of the aerosol mass yielded coefficients of variation of 12.7, 7.7 and 1.4% for the low, medium and high exposure groups, respectively. The variance in the endotoxin extraction protocols was highest for the ASTM method for the low, medium and high concentration trials. Low, medium and high endotoxin groups were statistically different (P < 0.001), but there were no statistical differences between extraction protocols within these exposure levels. CONCLUSIONS: ASTM method E2144-01 yielded comparable estimations of MWF endotoxin aerosol concentrations but with higher variability than the four other extraction methods. This study shows that extraction into PFW at 25 degrees C with or without Tween-20 was an improvement over the ASTM method in that the estimation was more precise and the method is simpler.

Aerosols↗

PubMedDate not supplied

Effects of bacterial endotoxins on neutrophil function.

The neutrophil is a key element in host resistance to bacterial infection. Bacterial products capable of subverting the antimicrobial properties of neutrophils can have a potentially deleterious effect on the host. Current knowledge of the effects of endotoxins derived from the outer cell envelope of gram-negative bacteria on neutrophil function is summarized. Available evidence indicates that endotoxins bind to neutrophils, both in vitro and in vivo. The lipid A region of the endotoxin macromolecule appears to be important in promoting the association of endotoxin with the neutrophil cell membrane. Endotoxin-neutrophil interactions can result in altered neutrophil adhesive and locomotory properties. Moreover, endotoxins have been demonstrated to induce selective degranulation of specific (secondary) granule constituents and to alter the oxidative and microbicidal properties of the neutrophil. Further studies are needed to define on a molecular level the nature of the endotoxin receptor, the precise structural components of endotoxin responsible for altering neutrophil behavior, and the transductional event(s) leading to neutrophil activation as a result of endotoxin exposure.

Animals↗

PubMed1985

Role of antibiotic class in the rate of liberation of endotoxin during therapy for experimental gram-negative bacterial sepsis.

To evaluate the role of antibiotic class in the rate of liberation of endotoxin during therapy for sepsis caused by gram-negative bacteria, we obtained serial blood samples from rabbits with sepsis caused by Escherichia coli and treated with chloramphenicol, gentamicin, or moxalactam. The concentrations of viable bacteria, free endotoxin, and total endotoxin in each blood sample were measured. In rabbits treated with chloramphenicol, the geometric mean levels of free endotoxin remained proportional to the geometric mean levels of bacteremia, a result indicating the absence of antibiotic-induced endotoxin liberation. In contrast, levels of free endotoxin increased rapidly while levels of bacteremia declined after treatment with gentamicin or moxalactam, a result indicating antibiotic-induced release of endotoxin. Despite similar rates of bacterial killing, mean levels of free endotoxin were as much as 20-fold higher in rabbits treated with moxalactam than in paired rabbits receiving gentamicin (P less than .05). These results indicate that endotoxin liberation during therapy for sepsis caused by gram-negative bacteria is dependent upon the class of antibiotic administered and is not necessarily correlated with the rate of bacterial killing.

Animals↗

PubMed2000

Endocrine alterations that underlie endotoxin-induced disruption of the follicular phase in ewes.

Two experiments were conducted to investigate endocrine mechanisms by which the immune/inflammatory stimulus endotoxin disrupts the follicular phase of the estrous cycle of the ewe. In both studies, endotoxin was infused i.v. (300 ng/kg per hour) for 26 h beginning 12 h after withdrawal of progesterone to initiate the follicular phase. Experiment 1 sought to pinpoint which endocrine step or steps in the preovulatory sequence are compromised by endotoxin. In sham-infused controls, estradiol rose progressively from the time of progesterone withdrawal until the LH/FSH surges and estrous behavior, which began approximately 48 h after progesterone withdrawal. Endotoxin interrupted the preovulatory estradiol rise and delayed or blocked the LH/FSH surges and estrus. Experiment 2 tested the hypothesis that endotoxin suppresses the high-frequency LH pulses necessary to stimulate the preovulatory estradiol rise. All 6 controls exhibited high-frequency LH pulses typically associated with the preovulatory estradiol rise. As in the first experiment, endotoxin interrupted the estradiol rise and delayed or blocked the LH/FSH surges and estrus. LH pulse patterns, however, differed among the six endotoxin-treated ewes. Three showed markedly disrupted LH pulses compared to those of controls. The three remaining experimental ewes expressed LH pulses similar to those of controls; yet the estradiol rise and preovulatory LH surge were still disrupted. Our results demonstrate that endotoxin invariably interrupts the preovulatory estradiol rise and delays or blocks the subsequent LH and FSH surges in the ewe. Mechanistically, endotoxin can interfere with the preovulatory sequence of endocrine events via suppression of LH pulsatility, although other processes such as ovarian responsiveness to gonadotropin stimulation appear to be disrupted as well.

Animals↗

PubMed1988

Corticosteroids inhibit endotoxin-induced lung lymph neutrophil stimulating activity in sheep.

The Adult Respiratory Distress Syndrome (ARDS) most frequently is the result of sepsis. Accumulation of neutrophils in lung interstitium is a well-documented phenomenon, but the nature of their presence remains obscure. We hypothesized that endotoxin causes the release of substances into lung lymph that activate neutrophils and that methylprednisolone may prevent sequestration and activation of neutrophils. We used the sheep lung lymph fistula-endotoxin model of ARDS to test this hypothesis. Unanesthetized animals were given either 0.5 microgram/kg of E. coli endotoxin intravenously alone or, on a different experimental day, an identical dose of endotoxin preceded by a 1 gm bolus of methylprednisolone plus a 1 gm/hr continuous infusion. Endotoxin infusion caused the release of substances into lung lymph that were capable of stimulating normal sheep neutrophils to aggregate, migrate, and release superoxide. This activity appeared within 1 hour of endotoxin and persisted for at least 4 hours. Pretreatment by methylprednisolone did not prevent the early activity but did significantly reduce such activity 3-4 hours after endotoxin, when the permeability defects caused by endotoxin are most pronounced. We speculate that endotoxin-stimulated production of humoral neutrophil-activating substances in the lung may play a role in the pathogenesis of acute lung injury.

Animals↗

PubMed1997

ONO-5046, an elastase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits.

Endotoxin causes acute lung injury resembling acute respiratory distress syndrome. Elastase, as well as reactive oxygen species released from activated neutrophils, are thought to play pivotal roles in the pathogenesis of this lung injury. This study investigated whether ONO-5046, a specific elastase inhibitor, can attenuate acute lung injury induced by endotoxin in rabbits. Thirty-two male anesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 for each group): infusion of saline without ONO-5046 treatment (Group S-S), infusion of saline with ONO-5046 (Group S-O), infusion of Escherichia coli endotoxin (100 micrograms/kg over 60 min) without ONO-5046 (Group E-S), and infusion of endotoxin with ONO-5046 (Group E-O). Fifteen minutes before the infusion of endotoxin (Groups E-O and E-S) or saline (Groups S-S and S-O), the animals received a bolus injection of ONO-5046 (10 mg/kg) followed by continuous infusion (10 mg.kg-1.h-1: Groups S-O and E-O) or saline (Groups S-S and E-S). The lungs of the rabbits were ventilated with 40% oxygen. Hemodynamics, peripheral leukocyte and platelet counts, and PaO2 were recorded during the ventilation period (6 h). Lung mechanics, cell fraction of the bronchoalveolar lavage fluid (BALF), activated complement, cytokines, and arachidonic acid metabolite concentrations in the BALF were measured at 6 h. The wet- to dry (W/D)-weight ratio of the lung and albumin concentrations in BALF were analyzed as indices of pulmonary edema. Endotoxin decreased lung compliance and PaO2, and increased the W/D weight ratio, neutrophil counts, and albumin concentration in the BALF. Concentrations of activated complement C5a, interleukin-6, interleukin-8, and thromboxane B2 in the BALF were increased by the infusion of endotoxin. ONO-5046 treatment attenuated these changes. Endotoxin caused extensive morphologic lung damage, which was lessened by ONO-5046. In conclusion, intravenous ONO-5046 pretreatment attenuated endotoxin-induced lung injury in rabbits. This beneficial effect of ONO-5046 may be due, in part, to a reduction in the levels of mediators that activate neutrophils, in addition to the direct inhibitory effect on elastase.

Airway Resistance↗

PubMed2000

Evaluation of low-dose endotoxin administration during pregnancy as a model of preeclampsia.

BACKGROUND: Recent evidence implicates nitric oxide (*NO) in the pathogenesis of preeclampsia. The authors tested the hypothesis that administration of low-dose endotoxin to pregnant rats mimics the signs of preeclampsia in humans and that *NO and *NO-derived species play a role in that animal model. METHODS: Endotoxin was infused at doses of 1, 2 and 10 microg/kg over 1 h to rats on day 14 of pregnancy. Mean arterial pressure, urinary protein, urinary and plasma nitrite plus nitrate (NO2- + NO3-) concentrations, and platelet count were measured before and after the endotoxin infusion. In another group of pregnant rats, the nitric oxide synthase inhibitor L-nitroarginine methyl ester (L-NAME) was administered in drinking water at a dose of 3 mg x kg(-1) x d(-1) starting on day 7 of pregnancy. Endotoxin was then infused at 10 microg/kg on day 14 of pregnancy. Kidneys and uteroplacental units were examined histologically and analyzed immunohistochemically for 3-nitrotyrosine. RESULTS: Endotoxin administration at doses of 2 and 10 microg/kg caused proteinuria and thrombocytopenia in pregnant rats, but did not result in hypertension. Urinary NO2- + NO3- concentration, reflective of tissue *NO production rates, was significantly elevated in pregnant rats that received endotoxin at 10 microg/kg. Ingestion of L-NAME caused hypertension. Tissues from pregnant rats treated with L-NAME, endotoxin at 10 microg/kg, and a combination of L-NAME and endotoxin had increased 3-nitrotyrosine immunoreactivity. CONCLUSION: Nitric oxide either directly or through secondary species plays a significant role in the biochemical and physiologic changes that occur in a rodent model of endotoxin-induced injury.

Animals↗