Protective effect of bactericidal/permeability-increasing protein (rBPI21) in baboon sepsis is related to its antibacterial, not antiendotoxin, properties.
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OBJECTIVE AND SUMMARY BACKGROUND DATA: The recombinant fragment of bactericidal/permeability-increasing protein, rBPI21, has potent bactericidal activity against gram-negative bacteria as well as antiendotoxin (lipopolysaccharide [LPS]) action. On the basis of these activities, the authors sought to discover whether rBPI21 would be protective in baboons with live Escherichia coli-induced sepsis and whether the potential protective effects of rBPI21 (together with antibiotics) would be more closely related to its antibacterial or LPS-neutralizing effects. METHODS: In a prospective, randomized, placebo-controlled subchronic laboratory study, the efficacy of rBPI21 or placebo was studied over 72 hours in chronically instrumented male baboons infused with live E. coli under antibiotic therapy. RESULTS: Intravenous rBPI21 attenuated sepsis-related organ failure and increased survival significantly. Bacteremia was significantly reduced in the rBPI21 group at 2 hours after the start of the E. coli infusion, whereas circulating LPS was less affected. The in vivo formation of tumor necrosis factor was significantly suppressed by the rBPI21 treatment regimen. Microcirculation and organ function were improved. CONCLUSIONS: In baboon live E. coli sepsis, the salutary effect of rBPI21 results from a more prevalent antibacterial than antiendotoxin activity. (+info)
Raf-1 is activated by the p38 mitogen-activated protein kinase inhibitor, SB203580.
(2/1830)
SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imi dazole) is widely used as a specific inhibitor of p38 mitogen-activated protein kinase (MAPK). Here, we report that SB203580 activates the serine/threonine kinase Raf-1 in quiescent smooth muscle cells in a dose-dependent fashion. The concentrations of SB203580 required lie above those necessary to inhibit p38 MAPK and we were unable to detect basal levels of active p38 MAPK. SB203580 does not directly activate Raf-1 in vitro, and fails to activate Ras, MEK, and ERK in intact cells. In vitro, however, SB203580-stimulated Raf-1 activates MEK1 in a coupled assay. We conclude that activation of Raf-1 by SB203580 is not mediated by an inhibition of p38 MAPK, is Ras-independent, and is uncoupled from MEK/ERK signaling. (+info)
The biological clock of very premature primate infants is responsive to light.
(3/1830)
Each year more than 250,000 infants in the United States are exposed to artificial lighting in hospital nurseries with little consideration given to environmental lighting cycles. Essential in determining whether environmental lighting cycles need to be considered in hospital nurseries is identifying when the infant's endogenous circadian clock becomes responsive to light. Using a non-human primate model of the developing human, we examined when the circadian clock, located in the hypothalamic suprachiasmatic nuclei (SCN), becomes responsive to light. Preterm infant baboons of different ages were exposed to light (5,000 lux) at night, and then changes in SCN metabolic activity and gene expression were assessed. After exposure to bright light at night, robust increases in SCN metabolic activity and gene expression were seen at ages that were equivalent to human infants at 24 weeks after conception. These data provide direct evidence that the biological clock of very premature primate infants is responsive to light. (+info)
Modulation of the baboon (Papio anubis) uterine endometrium by chorionic gonadotrophin during the period of uterine receptivity.
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This study was undertaken to determine the modulation of uterine function by chorionic gonadotrophin (CG) in a nonhuman primate. Infusion of recombinant human CG (hCG) between days 6 and 10 post ovulation initiated the endoreplication of the uterine surface epithelium to form distinct epithelial plaques. These plaque cells stained intensely for cytokeratin and the proliferating cell nuclear antigen. The stromal fibroblasts below the epithelial plaques stained positively for alpha-smooth muscle actin (alphaSMA). Expression of alphaSMA is associated with the initiation of decidualization in the baboon endometrium. Synthesis of the glandular secretory protein glycodelin, as assessed by Western blot analysis, was markedly up-regulated by hCG, and this increase was confirmed by immunocytochemistry, Northern blot analysis, and reverse transcriptase-PCR. To determine whether hCG directly modulated these uterine responses, we treated ovariectomized baboons sequentially with estradiol and progesterone to mimic the hormonal profile of the normal menstrual cycle. Infusion of hCG into the oviduct of steroid-hormone-treated ovariectomized baboons induced the expression of alphaSMA in the stromal cells and glycodelin in the glandular epithelium. The epithelial plaque reaction, however, was not readily evident. These studies demonstrate a physiological effect of CG on the uterine endometrium in vivo and suggest that the primate blastocyst signal, like the blastocyst signals of other species, modulates the uterine environment prior to implantation. (+info)
Induction of thioredoxin and thioredoxin reductase gene expression in lungs of newborn primates by oxygen.
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Thioredoxin (TRX) is a potent protein disulfide oxidoreductase important in antioxidant defense and regulation of cell growth and signal transduction processes, among them the production of nitric oxide. We report that lung TRX and its reductase, TR, are specifically upregulated at birth by O2. Throughout the third trimester, mRNAs for TRX and TR were expressed constitutively at low levels in fetal baboon lungs. However, after premature birth (125 or 140 of 185 days gestation), lung TRX and TR mRNAs increased rapidly with the onset of O2 or air breathing. Lung TRX mRNA also increased in lungs of term newborns with air breathing. Premature animals (140 days) breathing 100% O2 develop chronic lung disease within 7-14 days. These animals had greater TRX and TR mRNAs after 1, 6, or 10 days of life than fetal control animals. In 140-day animals given lesser O2 concentrations (as needed) who do not develop chronic lung disease, lung TRX and TR mRNAs were also increased on days 1 and 6 but not significantly on day 10. In fetal distal lung explant culture, mRNAs for TRX and TR were elevated within 4 h in 95% O2 relative to 1% O2, and the response was similar at various gestations. In contrast, TRX protein did not increase in lung explants from premature animals (125 or 140 days) but did in those from near-term (175-day) fetal baboons after exposure to hyperoxia. However, lung TRX protein and activity, as well as TR activity, eventually did increase in vivo in response to hyperoxia (6 days). Increases in TRX and TR mRNAs in response to 95% O2 also were observed in adult baboon lung explants. When TRX redox status was determined, increased O2 tension shifted TRX to its oxidized form. Treatment of lung explants with actinomycin D inhibited TRX and TR mRNA increases in 95% O2, indicating transcriptional regulation by O2. The acute increase in gene expression for both TRX and TR in response to O2 suggests an important role for these proteins during the transition from relatively anaerobic fetal life to O2 breathing at birth. (+info)
Localization of ubiquitin and ubiquitin cross-reactive protein in human and baboon endometrium and decidua during the menstrual cycle and early pregnancy.
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We have examined the distribution of ubiquitin and the related ubiquitin cross-reactive protein (UCRP) in paraffin-embedded sections of human and baboon endometrium and decidua by immunoperoxidase or immunofluorescence cytochemistry with antibodies raised against ubiquitin, UCRP, CD45, and insulin-like growth factor-binding protein-1. Anti-ubiquitin immunoreactivity was present in the nonpregnant endometrium, particularly in the glandular epithelial cells, and up-regulated in endometrial stromal cells as they decidualized at the beginning of pregnancy. Anti-UCRP immunoreactivity was absent from nonpregnant tissue but accumulated to high levels in decidual cells during pregnancy. Western blotting indicated that immunoreactivity was primarily due to the presence of ubiquitin and UCRP conjugated to other proteins, and that although levels of ubiquitin-protein conjugates do not change substantially during pregnancy, decidualization is accompanied by the appearance of conjugates of UCRP. Baboon uterine tissues demonstrated a similar distribution of the two proteins, which indicates that the baboon may be a useful model for study of the role of the ubiquitin system and UCRP in the establishment of pregnancy in humans. (+info)
Lymph and pulmonary response to isobaric reduction in plasma oncotic pressure in baboons.
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Plasma colloid osmotic pressure was reduced by 76% (from 19.6 +/- 0.6 to 4.7 +/- 1.5 mm Hg) in five baboons while pulmonary capillary hydrostatic pressure was maintained at a normal level. This resulted in fluid retention, weight gain, peripheral edema and ascites, but no pulmonary edema. Thoracic duct lymph flow increased 6-fold and pulmonary lymph flow 7-fold. Thoracic duct lymph had a lower colloid osmotic pressure (2.0 +/- 0.7 mm Hg) than plasma (4.7 +/- 1.5 mm Hg), whereas the colloid osmotic pressure of pulmonary lymph (4.7 +/- 0.7 mm Hg) was the same as that of plasma. The lymph-plasma ratio for albumin fell in thoracic duct lymph but remained unchanged in pulmonary lymph. The difference between plasma colloid osmotic pressure and pulmonary artery wedge pressure decreased from 15.3 +/- 1.9 to -0.7 +/- 2.9 mm Hg. Despite this increase in filtration force, the lungs were protected from edema formation by a decrease of 11 mm Hg in pulmonary interstitial colloid osmotic pressure and a 7-fold increase in lymph flow. (+info)
Cytotoxicity of human and baboon mononuclear phagocytes against schistosomula in vitro: induction by immune complexes containing IgE and Schistosoma mansoni antigens.
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Normal human blood monocytes, pre-incubated at 37 degrees C with sera from patients infected with Schistosoma mansoni, strongly adhered to S. mansoni schistosomula in vitro, whereas no significant adherence was induced by sera from uninfected individuals. Comparable adherence occurred with normal baboon blood monocytes or peritoneal macrophages when these cells were incubated with sera from S. mansoni-infected baboons. Adherence of macrophages to schistosomula was associated with damage to the larvae, as estimated by a 51Cr release technique. Neither adherence nor cytotoxicity was induced by pre-incubation of the schistosomula, instead of the monocytes, with immune serum. The relevant factor in immune serum was heat-labile, but was not a complement component. Absorption and ultracentrifugation experiments showed that immune complexes, containing S. mansoni-specific IgE antibody and soluble parasite antigens, produced monocyte or macrophage adherence and cytotoxicity. Similar observations have been reported previously in the rat model. Since the production of large amounts of IgE is a predominant feature of schistosome infections in man and experimental animals, it is possible that this new mode of mononuclear phagocyte activation could act as an immune effector mechanism against S. mansoni. (+info)