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PubMed2003

Peripheral administration of lipopolysaccharide enhances the expression of guanosine triphosphate cyclohydrolase I mRNA in murine locus coeruleus.

GTP cyclohydrolase I is the first and rate-limiting enzyme for the de novo biosynthesis of tetrahydrobiopterin, which is the cofactor for tyrosine hydroxylase. Lipopolysaccharide can modulate tetrahydrobiopterin production by upregulating GTP cyclohydrolase I protein expression in the locus coeruleus in the mouse brain. The increased supply of tetrahydrobiopterin in the locus coeruleus leads to increased tyrosine hydroxylase activity without affecting the level of tyrosine hydroxylase protein expression, resulting in an increase in norepinephrine turnover at the site. This study was performed to address whether the increase in GTP cyclohydrolase I protein is dependent on the de novo synthesis of GCH in the locus coeruleus. After i.p. administration of lipopolysaccharide, the mRNA expression of GTP cyclohydrolase I was examined. The expression level increased within 2 h, and reached to maximum level at 4 h after the lipopolysaccharide administration. However, the mRNA expression level of 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase, both of which are involved successively after GTP cyclohydrolase I in tetrahydrobiopterin biosynthesis, were not affected by the lipopolysaccharide administration. These results suggest that GTP cyclohydrolase I upregulation alone is enough to modulate tetrahydrobiopterin production in the locus coeruleus. In addition, the mRNA level of tyrosine hydroxylase was also not affected by the lipopolysaccharide administration. Taken together, the data indicate that GTP cyclohydrolase I plays a crucial role in regulating norepinephrine biosynthesis by a pathway the activity of which is triggered by lipopolysaccharide i.p. administration.

Alcohol Oxidoreductases↗

PubMed1983

Physical properties of defined lipopolysaccharide salts.

The electron spin resonance probes 5-doxylstearate and 4-(dodecyldimethylammonio)-1-oxy-2,2,6,6-tetramethylpiperidine bromide were used to characterize the fluidity of the acyl chain and head-group regions, respectively, of defined salts of lipopolysaccharide (LPS) from Escherichia coli K12. The removal of the weakly bound divalent cations from native LPS by electrodialysis and their replacement by sodium had little effect on the midpoint of the lipid-phase transition or on head-group mobility. In contrast, lipopolysaccharide acyl chain mobility increased following electrodialysis. The replacement of most of the remaining cations with sodium resulted in a further dramatic increase in mobility in both the polar and nonpolar regions of lipopolysaccharide. Head-group mobility of the sodium salt of LPS was shown to be reduced with the addition of divalent cations. Furthermore, evidence is presented which suggests that low magnesium concentrations may induce phase separations in the sodium salt. The magnesium salt of lipopolysaccharide closely resembled the native form in both head-group and acyl chain mobility although the cation charge to phosphorus ratio in the magnesium salt was greater than that detected in the native isolate. Analyses of other lipopolysaccharide salts support our hypothesis that many of the observed differences in the physical and pathological properties of lipopolysaccharide salts may simply be explained by the degree of charge neutralization.

Carbohydrate Conformation↗

PubMed2000

Involvement of calcium in the stimulation of phosphatidylcholine secretion in primary cultures of rat type II pneumocytes by Escherichia coli lipopolysaccharide.

The purpose of this study was to evaluate the mechanism by which Escherichia coli lipopolysaccharide stimulates the secretion of phosphatidylcholine in primary cultures of rat type II pneumocytes. The stimulatory effect of lipopolysaccharide on phosphatidylcholine secretion was additive to those of terbutaline and TPA (protein kinase A and C activators respectively) and this effect was not suppressed by inhibitors of both protein kinases. On the other hand, lipopolysaccharide did not modify the increase on phosphatidylcholine secretion induced by the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin, and enhanced slightly the calcium-ionophore A23187 stimulated phosphatidylcholine secretion. In addition, the stimulatory effect of lipopolysaccharide was suppressed by BAPTA, an intracellular Ca2+ chelator, and KN-62, a specific inhibitor of Ca2+-calmodulin-dependent protein kinase. These results, together with the lipopolysaccharide-mediated increase in the cytosolic [Ca2+], suggest that stimulation of phosphatidylcholine secretion by lipopolysaccharide in type II pneumocytes occurs by a calcium-dependent transduction mechanism via Ca2+-calmodulin-dependent protein kinase activation.

Adrenergic beta-Agonists↗

PubMed2001

A possible mechanism of maxillofacial abscess formation: involvement of Porphyromonas endodontalis lipopolysaccharide via the expression of inflammatory cytokines.

In a previous study, we developed a specific monoclonal antibody against Porphyromonas endodontalis lipopolysaccharide, and demonstrated that this lipopolysaccharide was detected in bacterially infected root canal fluid. We suggest here that P. endodontalis lipopolysaccharide in the infectious materials plays a stimulatory role in maxillofacial abscess formation via the expression of inflammatory cytokines. Our epidemiological study showed that this lipopolysaccharide was detected in significant levels the infectious material of patients with periapical periodontitis and odontogenic abscesses. Interestingly, infectious material-induced expression of tumor necrosis factor-alpha, interleukin-1beta, or neutrophil chemoattractant KC genes in mouse macrophages, was significantly neutralized by monoclonal antibody against the lipopolysaccharide. In addition, we also detected a significant amount of tumor necrosis factor-alpha in the infectious material. These results suggest that P. endodontalis lipopolysaccharide plays an important role in the pathogenic mechanism of maxillofacial abscess formation via the expression of inflammatory cytokines.

Adolescent↗

PubMed1965

The immunochemistry of Salmonella chemotype VI O-antigens. The structure of oligosaccharides from Salmonella group G (o 13,22) lipopolysaccharides.

1. Lipopolysaccharides have been isolated from ;smooth' (S) strains of Salmonella friedenau and Salmonella poona by the phenol-water method and purified in the preparative ultracentrifuge. 2. These lipopolysaccharides are serologically indistinguishable and on partial acid hydrolysis the same series of oligosaccharides was obtained in each instance. 3. The results of quantitative micro-analysis, borohydride reduction, periodate oxidation, Morgan-Elson reactions and enzymic hydrolysis with beta-galactosidase on the isolated oligosaccharides indicate that the O-specific side chains of these lipopolysaccharides have a repeating pentasaccharide unit that is beta-d-galactosyl-(1-->3)-N-acetylgalactosaminyl-(1-->3)-N-acetylgalactosaminyl-(1-->4)-l-fucose with a d-glucose residue bound at an undetermined point on this structure. 4. Two oligosaccharides, a glucosyl-galactose and an N-acetylglucosaminylglucose, have also been isolated and these seem to be identical with oligosaccharides obtained from ;rough' (R) Salmonella lipopolysaccharides. These findings are in accordance with the view that Salmonella S-lipopolysaccharides have a core that consists of R-lipopolysaccharide.

Antigens↗

PubMed1965

The immunochemistry of Salmonella chemotype VI O-antigens. The structure of oligosaccharides from Salmonella group N (o 30) lipopolysaccharides.

1. The lipopolysaccharides isolated from ;smooth' (S) strains of Salmonella godesberg and Salmonella urbana by the phenol-water method were purified in the ultracentrifuge. 2. These lipopolysaccharides have the same O-antigenic structure and on partial hydrolysis the same series of oligosaccharides was obtained in each instance. 3. The results of quantitative microanalysis, borohydride reduction, periodate oxidation, Morgan-Elson reactions and enzymic hydrolysis with alpha- and beta-glucosidases on the isolated oligosaccharides indicated that the O-specific side chains of these S-lipopolysaccharides have a repeating tetrasaccharide unit that is beta-d-glucosyl-(1-->3)-N-acetylgalactosaminyl-(1-->4)-l-fucose with a further glucose residue bound at the 4-position on the N-acetylgalactosamine. 4. Another oligosaccharide, a glucosylgalactose, has also been isolated and is indistinguishable from an oligosaccharide isolated from Salmonella R-lipopolysaccharides. These findings provide further evidence supporting the view that all Salmonella S-lipopolysaccharides have a core consisting of R-lipopolysaccharide.

Antigens↗

PubMed1965

The immunochemistry of Salmonella chemotype VI O-antigens. The structure of oligosaccharides from Salmonella group U (o 43) lipopolysaccharides.

1. A series of oligosaccharides was isolated from Salmonella milwaukee lipopolysaccharide by partial acid hydrolysis. 2. Structural studies on these oligosaccharides indicated that the O-specific side chain of this lipopolysaccharide has a repeating pentasaccharide unit that is probably alpha-d-galactosyl-(1-->3)-beta-d-galactosyl- (1-->3)-N-acetylgalactosaminyl-(1-->3)-N-acetyl- d-glucosaminyl-(1-->4)-l-fucose. 3. Another oligosaccharide, which is not structurally related to the repeating pentasaccharide unit, has also been isolated and it is indistinguishable from an oligosaccharide obtained from Salmonella ;rough' (R) lipopolysaccharides. The isolation of this and similar core oligosaccharides from all chemotype VI lipopolysaccharides supports the view that Salmonella S-lipopolysaccharides have a common core that is probably identical with RII lipopolysaccharide.

Antigens↗

PubMed1967

An extracellular lipopolysaccharide-phospholipid-protein complex produced by Escherichia coli grown under lysine-limiting conditions.

Lysine limitation during growth of the lysine-requiring mutant of Escherichia coli 12408 resulted in the excretion of a complex containing 60% of lipopolysaccharide, 26% of extractable phospholipid and 11% of protein. The complex was obtained from the culture filtrate in yields of about 0.5g./l. by precipitation with chloroform or gel filtration; some purification steps are described. The greater part of the phospholipid consisted of phosphatidylethanolamine, which contained four main fatty acids; two monoenoic acids and a cyclopropane acid were esterified mainly in the beta-position, and a saturated acid was located mainly in the gamma-position. The protein component was relatively insoluble and contained an excess of acidic over basic amino acids and little cystine. The lipopolysaccharide resembled in composition the intracellular lipopolysaccharides from rough strains of E. coli. Both protein and lipopolysaccharide constituents of the complex were serologically active; the complex was less toxic than the purified lipopolysaccharide. In the electron microscope the complex showed a mixture of particles of various sizes and shapes. Rods and hollow spheroids (diameter 12-200mmu) were most common and resembled the particles previously found surrounding cells actively excreting the complex. The chloroform-precipitated material showed a tubular lamellar structure. Soluble lipopolysaccharide prepared from the complex also consisted of hollow spheres and rods.

Bacterial Proteins↗

PubMed1999

Structural studies on lipopolysaccharides of serologically non-typable strains of Helicobacter pylori, AF1 and 007, expressing Lewis antigenic determinants.

In contrast to other Helicobacter pylori strains, which have serologically detectable Lewis(x)+ (Le(x)) and Lewis(y)++ (++Le(y)) antigenic determinants in the O-specific polysaccharide chains of the lipopolysaccharides, H. pylori AF1 and 007 were non-typable with anti-Le(x) and anti-Le(y) antibodies. The carbohydrate portions of the lipopolysaccharides were liberated by mild acid hydrolysis and subsequently studied by sugar and methylation analyses, 1H-NMR spectroscopy and electrospray ionization-mass spectrometry. Compared with each other, and with lipopolysaccharides of strains studied previously, the lipopolysaccharides of both AF1 and 007 showed similarities, but also differences, in the structures of the core region and O-specific polysaccharide chains. The O-specific polysaccharide chains of both strains consisted of a short or long polyfucosylated poly-N-acetyl-beta-lactosamine chains, which were distinguished from those of other strains by a high degree of fucosylation producing a polymeric Le(x)chain terminating with Le(x) or Le(y) units:[sequence: see text] where n = 0 or 1 in strain AF1 and 0 in strain 007, m = 0-2, 6-7 in strain AF1 and m = 0-2, 6-7 or approximately 40 in strain 007, the medium-size species being predominant. Therefore, compared with other strains, the lack of reactivity of lipopolysaccharide of H. pylori AF1 and 007 with anti-Le(x) and anti-Le(y) may reflect the presence of a polymeric Le(x) chain and has important implications for serological and pathogenesis studies. As the substitution pattern of a D-glycero-D-manno-heptose residue in the outer core varied in the two strains, and an extended DD-heptan chain was present in some lipopolysaccharide species but not in others, this region was less conservative than the inner core region. The inner core L-glycero-D-manno-heptose region of both strains carried a 2-aminoethyl phosphate group, rather than a phosphate group, as reported previously for other H. pylori strains.

Antigens, Bacterial↗

PubMed1996

Tetrahydrobiopterin biosynthesis enhanced by lipopolysaccharide stimulation in murine neuroblastoma cell line N1E-115.

We investigated for the first time the effect of lipopolysaccharide and the signal transduction pathway on the biosynthesis of tetrahydrobiopterin [(6R-L-erythro-1',2'-dihydroxypropyl) -2-amino-4-hydroxy-5,6,7,8-tetrahydropteridine], the cofactor for the enzymatic hydroxylation of the aromatic amino acids, in the murine neuroblastoma cell line N1E-115, which synthesizes tetrahydrobiopterin constitutively. Activation of N1E-115 cells with 1 microgram/ml lipopolysaccharide resulted in statistically significant increases in both intracellular tetrahydrobiopterin contents and the activity (Vmax) of GTP cyclohydrolase I, a rate-limiting enzyme in tetrahydrobiopterin de novo biosynthesis. Following simultaneous addition of the inhibitors of protein tyrosine kinases and GTP-binding proteins into serum-free culture media with lipopolysaccharide, we analyzed the transduction pathway of lipopolysaccharide signal toward the tetrahydrobiopterin biosynthetic system in N1E-115 cells. Our data indicate the following conclusions: (a) Protein tyrosine kinase systems are involved in mediating lipopoly-saccharide signal to tetrahydrobiopterin production, and (b) there may be a cross-talk between GTP-binding protein and the protein tyrosine kinase system in mediating lipopolysaccharide signal. These observations suggest that a neuronal cell such as N1E-115, which barely expresses CD14 on its cell surface, responds to lipopolysaccharide like macrophages and monocytes in the absence of soluble CD14.

Animals↗

PubMedDate not supplied

Effects of lipopolysaccharide on vascular reactivity and mortality in rats.

1 The effects of intraperitoneal (i.p.) lipopolysaccharide on vascular reactivity to noradrenaline in rat aorta under different conditions of passive tension, as well as on mortality in normotensive and hypertensive rats, were studied. 2 Concentration-response curves to noradrenaline were obtained in aorta rings, at two levels of passive tension: 3 and 0.5 g, from control and lipopolysaccharide-treated Wistar rats. Contractile responses were expressed as percentage of the maximal response to noradrenaline obtained in the beginning of the experiment at a resting tension of 2 g. The maxima were significantly larger (P<0.05) at 3 g than at 0.5 g in both groups of rats: 117.8 vs. 62.3%, respectively, for control animals; 85.8 vs. 32.5%, respectively, for lipopolysaccharide-treated rats. 3 The 24-h mortality after the i.p. administration of lipopolysaccharide was lower in spontaneously hypertensive rats (1/12; 8%), when compared with control Wistar-Kyoto rats (5/11; 45%). However, mortality was higher in Wistar-Kyoto made hypertensive by 8-day administration of corticosterone (6/6; 100%). 4 We conclude that a differential sensitivity to noradrenaline of aortic smooth muscle at two different levels of passive tension is still present in lipopolysaccharide-treated animals. Chronic hypertension in SHR rats is associated with resistance to the lethal effects of lipopolysaccharide, whereas abrupt-onset hypertension induced by corticosterone leads to an increased mortality. 5 These results are compatible with the myofibrillary hypothesis, which explains vascular hyper-reactivity in chronic arterial hypertension, by postulating that a more favourable relative position (and/or proportion) for actin and myosin occurs, whereas in states of vascular hyporeactivity, such as vasodilatory shock, the opposite phenomenon may exist.

Animals↗

PubMed2003

Platelet-activating factor antagonist WEB-2170 inhibits lipopolysaccharide-induced, but not antiprogestin-induced, preterm cervical ripening in timed-pregnant rats.

OBJECTIVE: The purpose of this study was to determine whether the platelet-activating factor antagonist WEB-2170 inhibits preterm cervical ripening induced by lipopolysaccharide or by antiprogestin RU 486. STUDY DESIGN: Timed-pregnant rats were killed on day 16 after treatment with (1) WEB-2170, lipopolysaccharide, lipopolysaccharide plus WEB-2170, or vehicle control and (2) with WEB-2170, RU 486, RU 486 plus WEB-2170, or vehicle control. Cervical ripening was assessed by light-induced fluorescence and resistance to stretch. Statistics were assessed by 1-way analysis of variance followed by Tukey-test (P <.05). RESULTS: Light-induced fluorescence and resistance to stretch were significantly lower in the lipopolysaccharide-treated and in the RU486-treated animals compared with vehicle control (lipopolysaccharide:light-induced fluorescence, 7.0+/-0.6 vs 12.8+/-0.8 [P=.001]; resistance to stretch, 0.41+/-0.03 N/mm vs 0.54+/-0.04 N/mm [P <.05]; RU486:light-induced fluorescence, 9.6+/-0.6 vs 11.7+/-0.6 [P <.05]; resistance to stretch, 0.28+/-0.06 N/mm vs 0.61+/-0.02 N/mm [P <.001]). Compared with vehicle control, WEB-2170 alone did not alter cervical light-induced fluorescence or resistance to stretch. Although WEB-2170 significantly blocked cervical ripening after lipopolysaccharide administration (light-induced fluorescence, 11.3+/-1.3 [P <.05]; resistance to stretch, 0.61+/-0.04 [P <.01]), WEB-2170 did not inhibit the RU 486-induced cervical ripening. CONCLUSION: Although infection-related cervical ripening is inhibited by platelet-activating factor antagonists, the physiologic process of cervical ripening appears to be unaffected. Platelet-activating factor inhibition may be of clinical value in the infection-related pathologic processes that are responsible for premature cervical ripening.

Animals↗

PubMed1982

Role of prostaglandin D2 in the hypothermia of rats caused by bacterial lipopolysaccharide.

The intraperitoneal administration of lipopolysaccharide from Salmonella typhimurium (1 mg/kg) caused a fall in the rat colonic temperature of about 2 degrees C at an ambient temperature of 22 +/- 3 degrees C. The hypothermia induced by the lipopolysaccharide was abated in a dose-dependent manner by the administration of indomethacin. Other inhibitors of prostaglandin synthetase such as aspirin, flufenamic acid, and phenylbutazone had effects similar to those of indomethacin. When various prostaglandins were injected intracerebroventricularly, only prostaglandin D2 caused a dose-dependent fall in the colonic temperature at doses between 1.2 and 6 nmol/kg. Microinjection of prostaglandin D2 into the preoptic area caused hypothermia of about 1 degree C. However, injection of prostaglandin D2 into the posterior hypothalamus had little effect on the colonic temperature. The hypothermia caused by prostaglandin D2 was not abated by the administration of indomethacin. The amount of prostaglandin D2 increased significantly in the preoptic/hypothalamic region of rat brain 1 hr after the intraperitoneal administration of the lipopolysaccharide, whereas such increase was not observed in rats pretreated with indomethacin. The in vitro incubation of the preoptic/hypothalamic slices with the lipopolysaccharide also increased the amount of prostaglandin D2. These results suggest that the intraperitoneal administration of the lipopolysaccharide induces the release of prostaglandin D2 in the preoptic/hypothalamic area of rat brain and that the latter compound is involved in the hypothermic response of rats to the lipopolysaccharide.

Animals↗

PubMed1996

Protein-tyrosine kinase activation is required for lipopolysaccharide induction of interleukin 1beta and NFkappaB activation, but not NFkappaB nuclear translocation.

In human monocytes, interleukin 1beta protein production and steady state mRNA levels are increased in response to lipopolysaccharide, predominantly as a result of increased transcription of the interleukin 1beta gene. Expression of interleukin 1beta and other cytokines, such as interleukin 6 and tumor necrosis factor alpha, has been shown to be dependent on the activation of the transcription factor, NFkappaB. Since recent studies have shown that lipopolysaccharide-induced tyrosine kinase activation is not required for NFkappaB nuclear translocation, we sought to determine whether NFkappaB translocated in the absence of tyrosine kinase activity was active in stimulating transcription. We have found that, in the human pro-monocytic cell line, THP-1, the lipopolysaccharide-induced expression of interleukin 1beta is dependent on tyrosine kinase activation. Tyrosine kinases are not required for lipopolysaccharide-mediated nuclear translocation of NFkappaB. However, in the absence of tyrosine kinase activity, the ability of NFkappaB to stimulate transcription is impaired. This inhibition of transcription is specific for NFkappaB; in the absence of tyrosine kinase activity, AP-1-dependent transcription is enhanced. These results suggest that, while lipopolysaccharide-induced expression of inflammatory mediators requires tyrosine kinase activity, tyrosine kinase activity is not obligatory for lipopolysaccharide signal transduction.

Base Sequence↗

PubMed2003

Lipopolysaccharide stimulates p38-dependent induction of antiviral genes in neutrophils independently of paracrine factors.

Lipopolysaccharide (LPS) induces neutrophils to synthesize and secrete pro-inflammatory cytokines and chemokines, which are regulated at both the transcriptional and translational level. We reported previously that neutrophils stimulated with LPS induce expression of genes typically expressed in response to stimulation with antiviral type I interferons (IFN), such as myxovirus resistance-1 (MX1). However, we present evidence that this response of neutrophils to lipopolysaccharide occurs in the absence of interferon-dependent signaling. Lipopolysaccharide-stimulated neutrophils do not phosphorylate the interferon-associated transcription factors signal transducer and activator of transcription-1 and -3, and medium from lipopolysaccharide-stimulated cells was unable to induce MX1 gene expression, suggesting a soluble factor is not involved. Furthermore, LPS did not alter expression of IFNA and IFNB genes. In contrast to neutrophils, LPS-stimulated human monocyte-derived macrophages induced the expression of MX1, but IFNB was induced, and medium from LPS-stimulated monocyte-derived macrophages supported MX1 induction. An inhibitor of p38 kinase blocked induction of MX1 by lipopolysaccharide, but not IFNalpha, in neutrophils, and induction of MX1 was dependent on protein synthesis. LPS, but not IFNalpha, substantially activated p38. In contrast, the induction of MX1 by LPS in monocyte-derived macrophages was insensitive to p38 inhibition, although p38 is phosphorylated in LPS-stimulated but not IFNalpha-stimulated monocyte-derived macrophages. The expression of MX1 in neutrophils and monocyte-derived macrophages is mediated by TLR4 but not TLR2. The data presented here indicate that lipopolysaccharide activates novel interferon-independent signaling pathways in neutrophils and that induction of antiviral genes is a consequence of exposure of neutrophils to bacterial products.

Antiviral Agents↗

PubMed2006

Elafin prevents lipopolysaccharide-induced AP-1 and NF-kappaB activation via an effect on the ubiquitin-proteasome pathway.

The serine anti-protease elafin is expressed by monocytes, alveolar macrophages, neutrophils, and at mucosal surfaces and possesses antimicrobial activity. It is also known to reduce lipopolysaccharide-induced neutrophil influx into murine alveoli as well as to abrogate lipopolysaccharide-induced production of matrix metalloprotease 9, macrophage inhibitory protein 2, and tumor necrosis factor-alpha by as-yet unidentified mechanisms. In this report we have shown that elafin inhibits the lipopolysaccharide-induced production of monocyte chemoattractant protein-1 in monocytes by inhibiting AP-1 and NF-kappaB activation. Elafin prevented lipopolysaccharide-induced phosphorylation of AP-1, c-Jun, and JNK but had no effect on phosphorylation of p38. The lipopolysaccharide-induced degradation of IL-1R-associated kinase 1, IkappaBalpha, and IkappaBbeta was inhibited by elafin but phosphorylation of IkappaBalpha was unaffected. Polyubiquitinated protein including polyubiquitinated IkappaBalpha was shown to accumulate in the presence of elafin. These results suggest that inhibition by elafin of lipopolysaccharide-induced AP-1 and NF-kappaB activation occurs via an effect on the ubiquitin-proteasome pathway.

Chemokine CCL2↗

PubMed1956

Increased resistance to infection and accompanying alteration in properidin levels following administration of bacterial lipopolysaccharides.

It has been shown that injection of lipopolysaccharides, derived from a variety of Gram-negative bacterial species, evokes in mice a rapidly developing rise in resistance to infection with Gram-negative pathogens. This is accompanied by an elevation in properdin titer, at times to levels 2 to 3 times the normal. The rate, magnitude, and duration of these responses are dependent on many factors, the most important of which are the quantity and timing of the lipopolysaccharide administered. The increased resistance to infection evoked in mice by lipopolysaccharides was effective against infections produced by endotoxin-bearing organisms-bacterial species highly susceptible in vitro to the bactericidal action of the properdin system. Properdin titers of mice prior to infection provide an incomplete picture of the subsequent reaction of the host to the infective agent. Following infection with Gram-negative organisms, properdin levels accurately reflect the bacteriologic course and outcome of the infection. Thus, in control animals, properdin titers progressively declined and the animals died, while in mice appropriately treated with lipopolysaccharide, properdin levels were either maintained in the normal range or increased, depending on the dose and time of administration of lipopolysaccharide; this was always accompanied by successful management of the infection. The complex nature of the alterations produced in the host by lipopolysaccharides is stressed. It is pointed out that the increase in the ability of the host to cope with Gram-negative infections may be the result of stimulation of other defense mechanisms, in addition to the properdin system.

Animals↗

PubMed2002

Myeloperoxidase-associated tyrosine nitration after intratracheal administration of lipopolysaccharide in rats.

BACKGROUND: Previous studies have shown that lipopolysaccharide-induced inflammation in the lung results in tyrosine nitration. The objective of this study was to evaluate the contribution of myeloperoxidase and peroxynitrite pathway to the tyrosine nitration in lipopolysaccharide-administered lungs of rats that were otherwise untreated or leukocyte-depleted by cyclophosphamide or received inhaled nitric oxide (NO). METHODS: The authors analyzed the immunoreactivity of inducible nitric oxide synthase (iNOS), nitrotyrosine (a product of the myeloperoxidase or peroxynitrite pathway), and chlorotyrosine (a byproduct of the myeloperoxidase pathway) by use of specific antibodies. The number of neutrophils in bronchoalveolar lavage fluid (BALF) and levels of myeloperoxidase activity in lung homogenates were also measured. RESULTS: Lipopolysaccharide enhanced the immunoreactivity of iNOS, nitrotyrosine, and chlorotyrosine in alveolar wall cells, alveolar macrophages, and neutrophils. Leukocyte depletion by cyclophosphamide and inhibition of leukocyte accumulation in the lungs by NO inhalation did not eliminate the increase in iNOS immunoreactivity in alveolar macrophages after lipopolysaccharide treatment, but nitrotyrosine and chlorotyrosine were not produced in these cells. Tyrosine nitration in response to lipopolysaccharide was associated with increases in neutrophil count in BALF and in myeloperoxidase activity in lung homogenates, whereas NO inhalation suppressed the neutrophil count in BALF and reduced tyrosine nitration and chlorination. CONCLUSIONS: These findings suggest that myeloperoxidase pathway has a role in tyrosine nitration in the lungs of lipopolysaccharide-treated rats, and that NO inhalation during early phase of inflammation does not increase but rather decreases tyrosine nitration and chlorination, possibly by reducing neutrophil sequestration.

Administration, Inhalation↗