Differential clearance and induction of host responses by various administered or released lipopolysaccharides.

The clearance and activity of different types of lipopolysaccharide (LPS) released during infection with Gram-negative bacteria were investigated. When highly purified preparations differing in their specific endotoxin activity were administered intravenously to mice, the clearance of rough (R)-form LPS preparations from Salmonella minnesota and Escherichia coli was much faster than that of a smooth (S)-form LPS preparation from Salmonella abortus equi, but slower than that of lipo-oligosaccharides (LOS) preparations from Bordetella pertussis and Helicobacter pylori. After intraperitoneal infection with 10(7) and 10(8) CFU E. coli O111:B4, relatively high levels of LPS were detected dose-dependently in the plasma of infected mice and persisted for a long time. In addition, plasma sCD14 levels in infected mice were higher than in LPS-administered mice. These results indicate that continuously higher levels of plasma LPS followed by stronger host responses occur during infection and suggest that these differences between LPS-administered and infected mice should be taken into consideration when analyzing host responses induced by LPS.

Mycobacterial cord factor, but not sulfolipid, causes depletion of NKT cells and upregulation of CD1d1 on murine macrophages.

Trehalose 6,6'-dimycolate (TDM, cord factor) has frequently been used as an adjuvant to stimulate antibody production. Although it also induces cellular immunity, detailed studies about the underlying events do not exist. To determine the kinetics of TDM-specific changes promoting a T helper 1 (Th1) response, we injected mice with TDM or 2,3,6,6'-tetraacyl trehalose 2'-sulfate (SL, sulfolipid), another mycobacterial trehalose-containing glycolipid without mycolic acid. TDM, but not SL, caused a strong increase in serum interferon-gamma (IFN-gamma) levels 2 days later, accompanied by expansion of natural killer (NK) cells. Subsequent TDM effects included depletion of normal-density CD4(+) NK1.1(+) TCRalpha/beta(intermediate) cells from day 7 on, upregulation of MHC class II and CD1d1 on macrophages (peaking on day 21), and an increased proportion of Th1 cells evident after 3 weeks. TDM, but not a similar glycolipid without mycolic acid, can therefore initiate a cascade of events starting with strong release of IFN-gamma and NK cell expansion, resulting in the appearance of macrophages activated for antigen presentation. Our data therefore provide the basis for optimized immunization schedules with TDM as the adjuvant component of a Th1 vaccine.

Suppression of lethal toxicity of endotoxin by biscoclaurine alkaloid cepharanthin.

Suppressive effects of Cepharanthin (CE) on lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) production followed by liver injury were investigated. Pretreatment with CE reduced limulus activity of LPS. Intraperitoneal treatment with CE 10 min before an i.v. challenge of LPS resulted in protection from LPS lethality in D-galactosamine (GalN)-sensitized BALB/c but not in C57BL/6 and C57BL/10ScSn mice. Treatment with CE before the LPS challenge significantly reduced serum TNF levels in a dose-dependent manner. The suppression was most effective when CE was administered 10 min before the LPS challenge. Increased levels of enzymes released from hepatocytes into the circulation, as a result of LPS-induced liver injury, were reduced by CE administration. Histological evaluation demonstrated that massive cell infiltration after severe injury developed in liver of mice injected with LPS plus D-GalN unless they were pretreated with CE. Apoptotic cells decreased by treatment with CE. Treatment with CE retarded lethal shock induced by an infection with 10(8) CFU Salmonella typhimurium deltaaroA mutant. These results suggest that action of CE is initiated through suppression of LPS-induced TNF production.

Urinary concentrations of heavy metals in healthy Japanese under 20 years of age: a comparison between concentrations expressed in terms of creatinine and of selenium.

Voided urine samples from 575 young Japanese under 20 years of age (297 males and 278 females including infants) and from 380 subjects (20-29 years old, 193 males and 187 females) were analyzed for levels of creatinine, selenium, zinc, cadmium and mercury. This investigation presents data regarding the normal urinary levels of these substances in age groups of 0-4, 5-9, 10-14, 15-19, and 20-29 years. Urinary levels of creatinine and cadmium showed remarkable increases with the age of the subjects, whereas that of selenium was constant at all ages under 20. Urinary concentrations of heavy metals were represented by creatinine and selenium ratios. Comparisons between these ratios revealed that selenium is an excellent index for representing the levels of the substances contained in a voided urine sample. Creatinine was not useful as an index for younger subjects, because the urinary concentration of this compound increased almost threefold as the subjects became older, up to 15 years of age.

Analysis of selenium metabolites in urine samples of minke whale (Balaenoptera Acutorostrata) using ion exchange chromatography.

1. To study the distribution of selenium metabolites in whale urine, an analytical methodology for separation and determination has been developed. 2. From whale urine, five selenium components, including trimethylselenonium ion were separated and determined by a combination of ion exchange chromatography and fluorometry. 3. The mean urinary selenium level of five minke whales was 1500 ng/ml, with a standard deviation of 400 ng/ml, i.e., about 30 times as high as that for humans.