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Biomedical subjects

P Tobias

Publications and source records attributed to P Tobias.

12 recordsLinked to original sources
PubMed2000

LPS and LAM activation of the U373 astrocytoma cell line: differential requirement for CD14.

CD14 is a membrane protein (mCD14) found on monocytes and neutrophils that is required for the innate immune response to lipopolysaccharide (LPS) and lipoarabinomannan (LAM). CD14 can also be found in serum as soluble CD14 (sCD14) that when bound to bacterial products, enables many non-CD14 bearing cells to be activated. Lipopolysaccharide binding protein (LBP) is a plasma protein that disaggregates and catalytically transfers LPS to CD14. To examine the role of CD14 and LBP in LAM-dependent activation, we used the U373 astrocyte cell line to stably express membrane-bound CD14 (U373-CD14). In serum-free conditions, U373-CD14 cells could respond to LAM stimulation as measured by expression of intracellular adhesion molecule-1 (ICAM-1). Vector control cells (U373-RSV) could not respond to LAM or LPS; but, upon the addition of serum as a source of soluble CD14, control U373-RSV cells could respond to LPS, but not LAM. Therefore, LAM can activate U373 cells only through membrane CD14 and not soluble CD14. We also demonstrate that this membrane CD14-dependent LAM response is greatly facilitated by the addition of LBP.

Astrocytoma↗
PubMed2000

MD-2 binds to bacterial lipopolysaccharide.

Many LPS binding proteins have been described, but the exact nature of the LPS receptors that signal cells remains unclear. MD-2 is a molecule that is found in association with Toll-like receptor 4, which has been shown to be a receptor for LPS. We have produced human MD-2 in baculovirus and tested it for LPS binding. MD-2 binds the lipid A region of LPS without the need for LPS binding protein. These data suggest that MD-2 may be binding LPS as part of the TLR4 receptor complex.

Animals↗
PubMed1999

Lipoproteins inhibit macrophage activation by lipoteichoic acid.

Regulation of lipid metabolism during infection is thought to be part of host defense, as lipoproteins neutralize endotoxin (LPS) and viruses. Gram-positive infections also induce disturbances in lipid metabolism. Therefore, we investigated whether lipoproteins could inhibit the toxic effects of lipoteichoic acid (LTA), a fragment of gram-positive bacteria. LTA activated RAW264.7 macrophage cells, stimulating production of tumor necrosis factor (TNF) in a dose-dependent matter, but produced less TNF than that seen after LPS activation. High density (HDL) or low density lipoprotein (LDL) alone inhibited the ability of LPS to stimulate TNF production, but had little effect on the activation by LTA. When a maximally effective dose of LTA was mixed with lipoproteins and 10% lipoprotein-depleted plasma (LPDP), the ability of LTA to stimulate macrophage production of TNF was inhibited. HDL, LDL, and the synthetic particle, Soyacal, when mixed with LPDP, were able to inhibit the ability of LTA to activate macrophages. Lipopolysaccharide-binding protein (LBP) substituted for LPDP in catalyzing lipoprotein neutralization of LTA by HDL. Antibody to LBP inhibited the ability of LPDP to induce LTA neutralization by HDL.Thus, lipoproteins can prevent macrophage activation by fragments from both gram-positive and gram-negative microorganisms.-Grunfeld, C., M. Marshall, J. K. Shigenaga, A. H. Moser, P. Tobias, and K. R. Feingold. Lipoproteins inhibit macrophage activation by lipoteichoic acid.

Animals↗
PubMed1998

Lung diffusing capacity and exercise in subjects with previous high altitude pulmonary oedema.

Subjects with a history of high-altitude pulmonary oedema (HAPE) have increased pulmonary artery pressure and more ventilation-perfusion (V'A/Q') inhomogeneity with hypoxia and exercise. We used noninvasive methods to determine whether there are differences in the pulmonary diffusing capacity for carbon monoxide (DL,CO) and cardiac output (Q') during exercise, indicative of a more restricted pulmonary vascular bed in subjects with a history of HAPE. Eight subjects with radiographically documented HAPE and five controls with good altitude tolerance had standard pulmonary function testing and were studied during exercise at 30 and 50% of normoxic maximal oxygen consumption (V'O2) at an inspiratory oxygen fraction of 0.14 and 0.21. DL,CO and Q' were measured by CO and acetylene rebreathing techniques. HAPE-resistant subjects had 35% greater functional residual capacity than HAPE-susceptible subjects. Vital capacity and total lung capacity were also 7-10% greater. There were no differences in airflow rates or resting diffusing capacity. However, DL,CO in HAPE-susceptible subjects was lower in hypoxia and with exercise, and showed less increase (32 versus 49%) with the combined stimulus of hypoxic exercise. HAPE-susceptible subjects had smaller increases in stroke volume, Q', and ventilation during exercise. The findings are consistent with lower pulmonary vasoconstriction, greater vascular capacitance and greater ventilatory responsiveness during exercise in subjects who are resistant to high-altitude pulmonary oedema. Their larger lung volumes suggest a constitutional difference in pulmonary parenchyma or vasculature, which may be a determinant of high-altitude pulmonary oedema resistance.

Adult↗
PubMed1993

Lipopolysaccharide (LPS) recognition in macrophages. Participation of LPS-binding protein and CD14 in LPS-induced adaptation in rabbit peritoneal exudate macrophages.

Exposure of rabbit peritoneal exudate macrophages (PEM) or whole blood to picomolar concentrations of LPS induces adaptation or hyporesponsiveness to LPS. Because of the importance of plasma LPS-binding protein (LBP) and the macrophage cell membrane protein CD14 in recognition of LPS, we examined the effect of LBP on LPS-induced adaptation in PEM. PEM exposed to LPS in the presence of LBP for 8 h were markedly less responsive to subsequent stimulation by LPS than monocytes/macrophages (M phi) adapted in the absence of LBP. LPS-induced expression of TNF was sharply reduced in LBP-LPS-adapted PEM, but in contrast these cells remained fully responsive to Staphylococcus aureus peptidoglycan. We considered that specific hyporesponsiveness in LPS-adapted M phi or in blood monocytes could be due to decreased expression of CD14 or diminished binding of LBP-LPS complexes to CD14. However, flow cytometry analysis revealed only minimal reduction of CD14 expression or CD14-dependent binding of a fluorescent LPS derivative when normo- and hyporesponsive cells were compared. These results show that complexes of LPS and LBP are more effective than LPS alone in inducing adaptation to LPS, and LPS-induced hyporesponsiveness probably results from changes in cellular elements distinct from CD14 that are involved in either LPS recognition or LPS-specific signal transduction.

Acclimatization↗
PubMed1991

Regulatory mechanisms of host responsiveness to endotoxin (lipopolysaccharide).

During Gram-negative endotoxemia, precise regulation of monocyte/macrophage (M phi) responsiveness to lipopolysaccharide (LPS) is critical to preserve host defense while avoiding complications such as organ failure and death. We will discuss regulation of LPS-M phi interactions by LPS-binding plasma proteins and by LPS-induced changes in M phi responsiveness. Upon exposure to plasma, LPS binds to either lipoproteins or LPS-binding protein (LBP; a 60-kilodalton glycoprotein with a high-affinity binding site for the lipid A moiety of rough and smooth LPS). The LPS-LBP complex stimulates the M phi by binding to its cellular receptor, CD14 (a monocyte/M phi-specific, phosphatidylinositol-anchored surface glycoprotein). Pretreatment of whole blood with anti-CD 14 monoclonal antibody reduces the responsiveness of monocytes to LPS [determined by tumor necrosis factor-alpha (TNF-alpha) release]at least 10-fold. Similarly, cellular responsiveness to LPS is diminished at least 100-fold by depletion of plasma LBP with anti-LBP antibody. Compared to LPS-LBP induction of TNF-alpha, LPS-lipoprotein complexes are as much as 10,000-fold less active. Thus, partitioning of LPS between LBP and lipoproteins markedly influences M phi responsiveness to LPS. LPS also directly induces M phi hyporesponsiveness to itself by a process known as adaptation; exposure of M phi to less than or equal to LPS/ml (subthreshold for TNF induction) for 6-9 reduces the sensitivity of the M phi to subsequent challenge up to 1,000-fold, so that 1 microgram/ml rather than 1 ng/ml of LPS is required for maximal induction of TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Proteins↗
PubMed1990

Priming of polymorphonuclear granulocytes by lipopolysaccharides and its complexes with lipopolysaccharide binding protein and high density lipoprotein.

Human peripheral blood neutrophils are primed, or enabled to respond to formyl peptide, by prior exposure to bacterial lipopolysaccharide (LPS). The activity of LPS and the size of its aggregates are altered by plasma constituents such as high density lipoprotein (HDL) and the recently discovered acute phase reactant lipopolysaccharide binding protein (LBP) Tobias et al.: J. Exp. Med. 164,777, 1986]. The ability of LPS, LPS-LBP, and LPS-HDL complexes to activate a number of cellular responses have been compared. LPS-LBP and LPS-HDL were prepared using LBP and HDL from rabbit serum. LPS from Salmonella minnesota Re595 and its LPS-LBP and LPS-HDL complexes differed in their ability to prime PMN O2- production in response to formyl peptide (f-Nle-Leu-Phe-Nle-Tyr-Leu [FNLPNTL]). Human PMN prepared under conditions in which O2- production is minimal (less than 1 nmol O2-/10(6) PMN/10 min) after exposure to 10(-7) M FNLPNTL can be primed with 0.1-100 ng/ml LPS in a dose- and time-dependent manner to produce up to 12 nmol O2-/10(6) PMN/10 min. LBP complexation accelerated the priming induced by LPS, whereas HDL complexation retarded it. Priming was accompanied by a parallel two- to threefold increase in formyl peptide receptor number as determined by FACS analysis of fluoresceinated FNLPNTL binding and SDS-PAGE autoradiographic analysis of photoaffinity ligand binding. Thus binding of LPS to plasma proteins changes the response of the PMS to LPS and may represent one way in which the response of the PMN is regulated during infection. Since LBP concentrations change during an acute phase response, complexation of LPS with LBP is a mechanism that may regulate neutrophil responses in vivo during inflammation.

Acute-Phase Proteins↗
PubMed1988

Inhibition of lipopolysaccharide activation of 7OZ/3 cells by anti-lipopolysaccharide antibodies.

We have investigated the ability of mAb against LPS to inhibit LPS-induced activation of 7OZ/3 pre-B cells. The fine specificity and relative affinity of these mAb for lipid A and LPS were also determined. We found that antibodies inhibited only the activity of glycolipids which they bound with relatively high affinity. However, two high affinity antibodies binding to non-lipid A epitopes did not block cellular activation. Some, but not all, relatively high affinity antibodies binding to the lipid A region of the LPS molecule inhibited biologic activity. The inhibitory antibodies bound to at least two distinct epitopes within the lipid A region. These data suggest that LPS interacts with 7OZ/3 cells in a highly specific fashion.

Animals↗
PubMed1982

Ranitidine in the treatment of gastric ulceration.

Seventy-two patients with endoscopically proven gastric ulcers were entered into a prospective controlled trial to assess the efficacy of ranitidine and cimetidine in ulcer healing. All patients were biopsied on entry and at subsequent endoscopies. After exclusion of 7 patients during the first month of treatment, the remaining 65 patients, 47 males and 18 females, mean age 48.2 +/-1.5 years, at 1 month had a healing rate of 47% and 52% respectively. The non-healers continued their treatment for a further 4 weeks. This increased the healing rate to 77% and 76% respectively. If the defaulters and poor compliers are withdrawn the healing rate rises to 58% and 57% at 4 weeks and to 91% and 79% at 8 weeks respectively. There was no significant difference between the two groups as regarded initial ulcer size and severity of dyspepsia. Antacid tablet consumption during the study was comparable. The initial size of the ulcers which failed to heal after 4 weeks of treatment tended to be larger than those which healed (P less than 0.05), but smoking did not appear to influence ulcer healing. No obvious side-effects or evidence of dysplasia were found. The study shows that ranitidine is at least as effective as cimetidine in gastric ulcer healing.

Aged↗