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Biomedical subjects

F H Valone

Publications and source records attributed to F H Valone.

At least 37 records · Page 2Linked to original sources
PubMed1990

Synergistic increases in IL-1 synthesis by the human monocytic cell line THP-1 treated with PAF and endotoxin.

The capacity to stimulate cytokine release may be important to the long-term effects of platelet-activating factor (PAF), which has a very short half-life. Previous studies have shown that PAF stimulates interleukin 1 (IL-1) release by human monocytes. IL-1 and other cytokines produced in response to PAF may be important to the long-term effects of this short-lived lipid. The THP-1 human monocytic leukemia cell line, was used to study the mechanism by which PAF stimulates IL-1 release. PAF stimulates the release of IL-1 beta activity into THP-1 cell supernatants with a multiphasic dose-response curve very similar to that for monocytes. When THP-1 cells are treated with PAF and LPS in combination, these two stimuli interact synergistically to greatly increase the release of IL-1 activity. To assess the effect of PAF on IL-1 beta synthesis, THP-1 cell pellet proteins were separated by SDS-PAGE, blotted, and immunostained to detect IL-1 beta. Immunostaining revealed that PAF increases intracellular IL-1 beta precursor and that the combination of PAF and LPS increases IL-1 beta precursor synergistically. PAF increases IL-1 beta release mainly by increasing IL-1 beta synthesis.

Blotting, Western↗
PubMed1990

Binding of viridans group streptococci to human platelets: a quantitative analysis.

The binding of viridans group streptococci with human platelets was analyzed by two-color flow cytometry. Binding was detected within 15 s of mixing bacteria and platelets. At ratios of bacteria to platelets of 1:1, 10:1, 100:1, and 1,000:1, the percentages of bound streptococci (mean +/- standard deviation) were 93.2% +/- 5.4%, 80.0% +/- 8.6%, 39.8% +/- 11.1%, and 12.5% +/- 2.0%, respectively. Binding of labeled bacteria was reversed by adding a 500-fold excess of unlabeled streptococci. These results demonstrate that streptococcus-platelet binding is rapid, reversible, and saturable, which suggests a specific receptor-ligand interaction.

Blood Platelets↗
PubMed1989

Late appearance of phospholipid platelet-activating factor and leukotriene B4 in human skin after repeated antigen challenge.

Inflammatory mediators were assessed in supernatants of chamber fluids from eight ragweed- or grass-sensitive subjects during antigen-induced cutaneous inflammatory responses. Platelet activating factor (PAF) accumulated at concentrations of 1 pm to 90 mumol/L in six of eight subjects beginning at 3 hours and continuing for 9 hours after antigen challenge. Leukotriene B4 (LTB4) was detectable at cutaneous sites of antigen challenge in five of five subjects throughout the 9-hour period at levels from 1 to 36 nmol, a range of 38% to 80% of which were omega-oxidation metabolites. Histamine levels peaked in the first hour at 106 +/- 18 ng/ml and decreased to a plateau of 11 to 13 ng/ml at 3 to 9 hours after antigen challenge. No PAF and only very low levels of LTB4 (0.1 to 1.3 nmol) and of histamine (less than 2 ng/ml) were detected at buffer-control sites during the 9 hours of study. Continuous antigen exposure thus results in the persistent release of histamine and LTB4 and the late appearance of PAF, all of which may contribute to the chronicity of allergic disorders and may have a bearing on the IgE-mediated, late-phase cutaneous response.

Adult↗
PubMed1989

Anaphylactoid reactions to vascular graft material presenting with vasodilation and subsequent disseminated intravascular coagulation.

This report describes five patients who had immediate adverse reactions following placement of a vascular graft. All had unusually persistent decreases in systemic vascular resistance, and four of these patients had bleeding as an early manifestation of this reaction. In two of three patients in whom the graft was replaced, uneventful recovery followed. Both patients in whom the graft was not replaced died. Blood samples from two of the patients demonstrated activation of complement and of the kinin system, whereas control patients did not demonstrate increased levels of activation products from these cascade systems. Recognition of this syndrome is important to patient survival, which appears to depend on rapid replacement of the graft.

Aged↗
PubMed1989

Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group.

We compared the effectiveness of fluorouracil (5-FU) alone (arm A), high-dose leucovorin plus 5-FU (arm B), and sequential methotrexate, 5-FU, and leucovorin (arm C) for treatment of patients with advanced colorectal carcinomas who had not received prior chemotherapy. Arm A consisted of infusions of 5-FU at 12 mg/kg/d intravenously (IV) for 5 days followed by weekly infusions of 5-FU at 15 mg/kg; arm B consisted of leucovorin infusions at 200 mg/m2/d IV plus infusions of 5-FU at 400 mg/m2/d IV on days 1 through 5 of a 28-day cycle; arm C consisted of methotrexate at 50 mg/m2 orally every 6 hours for five doses followed by infusions of 5-FU, 500 mg/m2 IV, and leucovorin, 10 mg/m2 orally, every 6 hours for five doses every other week. A total of 265 patients were entered into the trial, of whom 249 (94%) were fully evaluable. The objective response rate (complete [CR] plus partial [PR] responses) was 17.3% on arm A, 18.8% on arm B, and 19.8% on arm C (log-rank test, P greater than .4). The median time to failure was 138 days on arm A, 166 days on arm B, and 182 days on arm C (log-rank test, P values of arm A v B = .06; arm A v arm C = .04). Median survival was 345 days on arm A, 324 days on arm B, and 356 days on arm C (log-rank test, P greater than .4). Treatment with 5-FU alone was significantly more dose intensive and more toxic than either of the experimental combinations. The rates of grade 3 or greater nonhematologic toxicity were 42.3% on arm A, 24.3% on arm B, and 14.3% on arm C. Hematologic toxicity was milder but had the same pattern. This study indicates that these regimens of high-dose leucovorin plus 5-FU and sequential methotrexate, 5-FU, and leucovorin are not more effective than is 5-FU alone for treatment of patients with colorectal carcinomas when 5-FU is administered at high-dose intensity.

Adult↗
PubMed1988

Biphasic platelet-activating factor synthesis by human monocytes stimulated with IL-1-beta, tumor necrosis factor, or IFN-gamma.

The capacity of IL-1-beta, TNF, and IFN-gamma to stimulate platelet-activating factor (PAF) synthesis by human monocytes is examined in our report. All three cytokines induced PAF synthesis in a novel biphasic pattern with peaks of PAF synthesis 1 to 2 and 6 to 8 h after stimulation of the monocytes. In contrast, calcium ionophore A23187 elicited a single peak of early PAF synthesis. PAF in the early peak was largely retained intracellularly whereas PAF in the late peak was largely released into culture fluids. Combinations of cytokines were subadditive or antagonistic in inducing PAF synthesis. Cycloheximide inhibited the late peak of PAF synthesis indicating that protein synthesis is required for synthesis of the phospholipid PAF. Specific antibodies to TNF or IL-1-beta inhibited the late peak of PAF synthesis induced by IFN-gamma indicating that late PAF synthesis is dependent on cytokine synthesis. The quantities of PAF produced by cytokine-activated monocytes are sufficient to activate human monocytes. Thus, these studies suggest that PAF may mediate in part monocyte activation by cytokines.

Adult↗
PubMed1988

Platelet-activating factor binding and metabolism during human platelet aggregation.

Platelet-activating factor (PAF) binding and metabolism were quantified during human platelet aggregation induced by [3H]PAF. Platelet aggregation was maximal within 45 to 75 sec. PAF binding was maximal within 15 to 60 sec and then remained stable for at least 20 min. Total binding during aggregation elicited by 1.2 pmol [3H]PAF was 13.4% +/- 1.0% (0.16 +/- 0.01 pmol/8 x 10(7) platelets) (mean +/- SEM) and specific, receptor binding was 4.3% +/- 0.3% (0.05 +/- 0.003 pmol/8 x 10(7) platelets). Specific binding was fully reversible at the time of maximal aggregation. Scatchard analysis of PAF binding at the time of maximal platelet aggregation revealed 124 +/- 56 receptors per platelet with a dissociation constant of 0.56 +/- 0.04 nM. Binding of 52 +/- 23 PAF molecules per platelet elicited maximal platelet aggregation (mean +/- SD). Less than 2% of the bound PAF was metabolized at the time of maximal aggregation and the principal metabolite was the inactive product lysoPAF. Increased metabolism to alkyl-acyl-glycero-3-phosphocholine was observed at later times. These studies indicate that PAF receptor internalization and PAF metabolism are not essential to human platelet activation by PAF.

Binding, Competitive↗
PubMed1988

Identification of platelet-activating factor receptors in P388D1 murine macrophages.

Platelet-activating factor (PAF) binding and metabolism by eight murine and human cell lines was analyzed. Only the murine P388D1 macrophage line had specific, high affinity PAF binding sites. PAF binding reached saturation within 10 min at room temperature and was irreversible. Minimal PAF metabolism was observed at the time binding saturation was achieved. Scatchard analysis of PAF binding revealed a single class of PAF receptors (7872 +/- 1310/cell) which had a dissociation constant of 0.08 +/- 0.01 nM (mean +/- SEM, eta = 6). The dissociation constant was confirmed independently by quantifying the kinetics of initial specific PAF binding. PAF binding was stereospecific, required an sn-2 acetyl substituent, and was inhibited by structurally diverse PAF antagonists including kadsurenone, BN 52021, triazolam, and CV3988. The fact that the receptors are functionally active was shown by the observation that 1 to 100 pM PAF increased free intracellular calcium in P388D1 cells in a dose-related manner. These studies demonstrate that P388D1 macrophages have functional PAF receptors whose affinity and structural specificities are similar to PAF receptors in other cells. The availability of a stable cell line that binds but does not metabolize PAF will greatly facilitate studies of the PAF receptor.

Animals↗
PubMed1988

Distinctive patterns of release of neuroendocrine peptides after nasal challenge of allergic subjects with ryegrass antigen.

The concentrations of the neuropeptides substance P, somatostatin, and calcitonin gene-related peptide in human nasal secretions were quantified by radioimmunoassays, concurrently with that of histamine, in the course of nasal challenge of allergic and control subjects with ryegrass antigen to examine contributions of neuromediation of the tissue response. Each of the neuropeptides and histamine were detected in nasal lavage fluid prior to challenge. In allergic patients, but not normal controls, antigen evoked significant increases of 3-fold in histamine at 15-60 min, 1.5- to 4-fold in calcitonin gene-related peptide at 15 min-24 hr, and more than 2-fold in somatostatin at 6 hr, without altering the concentration of substance P in nasal lavage fluid. The identity of the neuropeptides was confirmed chromatographically. Thus calcitonin gene-related peptide may mediate nasal congestion directly and somatostatin may be one of the factors regulating the late involvement of basophils and mast cells in allergic rhinitis.

Administration, Intranasal↗
PubMed1988

Technetium-99m labeled 50H.19 antibody fragments: interaction of the antibody with platelets.

The monoclonal antibody 50H.19 recognized three antigens (Mr = 31-, 40-, 45-K) on normal and thromboasthenic platelets, but only one (Mr = 31-K) on Bernard-Soulier platelets. The intact antibody and its F(ab')2 fragments, had direct platelet-aggregating activity, and induced the platelet release reaction. The intact antibody potentiated platelet aggregation induced by platelet-activating factor or thrombin. Additions of indomethacin did not inhibit aggregation: addition of PGI2, or a calcium channel blocker completely inhibited aggregation. A reduced amount of platelet-aggregating activity was observed with antibody fragments prepared for labeling with 99mTc by pre-exposure to stannous ions, and herein used in biodistribution studies and elsewhere in thrombus imagining studies (J. Nucl. Med. 27: 1315; 1986). Antibody fragments radiolabeled with 99mTc bound to isolated platelets and to clots containing platelets.

Antibodies, Monoclonal↗
PubMed1988

Role of immunoglobulin G in platelet aggregation by viridans group streptococci.

The aggregation of human platelets by the viridans group streptococci requires both direct platelet-bacterium binding and plasma components. Some of these extracellular constituents (e.g., fibrinogen) are cofactors for ADP, which mediates the terminal events in platelet activation by these organisms. In addition, other plasma components which are specific for viridans group streptococci are necessary. To better define these latter cofactors, we examined the role of immunoglobulin G (IgG) in platelet aggregation by two strains of viridans group streptococci. The addition of either strain to washed human platelets suspended in normal plasma resulted in a 5- to 12-min lag phase, followed by brisk and irreversible platelet aggregation. In contrast, neither strain aggregated platelets suspended in IgG-depleted plasma (IgG concentration, less than or equal to 6.7 micrograms/ml). The addition of IgG (1.0 mg/ml) to the platelet suspension restored normal aggregation. Absorption of the IgG with intact bacteria abolished its ability to support aggregation. Preincubation of washed platelets with a murine monoclonal antibody to the 40,000-Mr platelet Fc receptor blocked aggregation by both strains, but had no effect on aggregation by ADP (5 microM) or collagen (200 micrograms/ml). Neither strain aggregated gel-filtered platelets supplemented with fibrinogen (100 micrograms/ml), whereas ADP induced a maximal platelet response. When IgG (1.0 mg/ml) was added to the suspension of gel-filtered platelets, both strains produced normal aggregation. These results indicate that specific IgG is required for platelet aggregation by viridans group streptococci and that platelet activation is mediated through the 40,000-Mr Fc receptor on the platelet surface.

Antigens, Differentiation↗
PubMed1988

Enhanced human monocyte cytotoxicity by platelet-activating factor.

The capacity of platelet-activating factor (PAF) to enhance human monocyte cytotoxicity for WEHI 164 cells was examined. Spontaneous monocyte cytotoxicity was 24 +/- 2% (mean +/- SEM, n = 9). Preincubation of monocytes with 1 pM-1 nM PAF for 18 hr significantly enhanced cytotoxicity in a dose-related manner, whereas less enhancement was observed at PAF concentrations above 1 nM. Maximal PAF-induced cytotoxicity was 68 +/- 6%, which was similar to that induced by optimal concentrations of tumour necrosis factor (TNF) and interferon-gamma. The specific PAF antagonist kadsurenone inhibited PAF-induced cytotoxicity but not TNF-induced cytotoxicity. The inactive PAF analogues lysoPAF and enantioPAF did not increase monocyte cytotoxicity. Two observations suggest that TNF mediates PAF-induced cytotoxicity: specific anti-TNF antibodies inhibited PAF-induced cytotoxicity toward WEHI 164 cells, and PAF did not enhance cytotoxicity to TNF-resistant cells. PAF represents a distinct class of phospholipid monocyte activators that increase monocyte cytotoxicity by TNF-dependent mechanisms.

Benzofurans↗
PubMed1987

Modulation of platelet-activating-factor-induced calcium influx and intracellular calcium release in platelets by phorbol esters.

The mechanisms by which platelet-activating factor (PAF) and thrombin increase intracellular calcium were examined. Platelets were loaded with the calcium-sensitive fluorescent probe Quin 2 and then were suspended in buffer containing 0.5 mM-Mn2+ in order to quantify simultaneously calcium release from intracellular stores and divalent cation influx. Pretreating platelets with agents which activate protein kinase C [the phorbol ester phorbol myristate acetate (PMA) or the diacylglycerol 1-oleoyl-2-acetylglycerol (OAG)] inhibited increased intracellular calcium by PAF and thrombin in a dose-related manner. That protein kinase C regulates intracellular calcium by phosphorylating proteins in two distinct pathways was suggested by two observations. PAF-induced calcium release was more sensitive to inhibition by PMA and OAG than was manganese influx and the kinetics of recovery from inhibition were different for the two pathways. Both PMA and OAG aggregated Quin 2-loaded platelets without eliciting measurable increases in intracellular calcium. In contrast, prostacyclin, which increases intracellular cyclic AMP, inhibited calcium release and influx in parallel, suggesting that this agent acts at a step common to both pathways.

Blood Platelets↗
PubMed1987

Inhibition of platelet-activating factor binding to human platelets by calcium channel blockers.

Calcium channel blockers may impair cell activation either by inhibiting calcium influx or by inhibiting agonist binding. Because of this dual action of calcium channel blockers and because of the close relationship between calcium influx and platelet-activating factor (PAF) binding to platelets the current studies examined the effect of calcium channel blockers on PAF binding to washed human platelets. Diltiazem and verapamil inhibited aggregation by PAF in a dose-dependent manner with 50% inhibition at 2.8 +/- 1.4 X 10(-5) M diltiazem (mean +/- SD, n = 5) and 4.2 +/- 2.0 X 10(-5) M verapamil. Both channel blockers also inhibited PAF binding in a dose-dependent manner with 50% inhibition at 4.7 +/- 2.5 X 10(-5) M diltiazem and 6.3 +/- 1.2 X 10(-5) M verapamil. Analysis of the mechanisms of inhibition of binding indicate both competitive and non-competitive effects of the channel blockers. Scatchard analysis of PAF binding in the presence of different fixed concentrations of either diltiazem or verapamil revealed that these agents both increased PAF receptor number and decreased the receptor binding affinity. Lineweaver-Burke analysis of the same data revealed a family of lines which intersect to the right of the ordinate. The channel blockers also dissociated previously-bound PAF from platelets. The current studies indicate that calcium channel blockers inhibit platelet activation by PAF by more than one mechanism and suggest that the PAF receptor may be closely associated with calcium channels.

Adult↗
PubMed1987

Preferential human eosinophil chemotactic activity of the platelet-activating factor (PAF) 1-0-hexadecyl-2-acetyl-sn-glyceryl-3-phosphocholine (AGEPC).

The chemotactic responses of human blood neutrophils and of eosinophils of two different densities, which were resolved by centrifugation on gradients of polyvinylpyrrolidone-coated silica gel (Percoll), were quantified in modified Boyden micropore filter chambers using highly purified synthetic 1-0-hexadecyl-2-acetyl-sn-glyceryl-3-phosphocholine (AGEPC or PAFacether) and leukotriene B4 (LTB4) as stimuli. Maximal chemotactic responses of the densest eosinophils, less dense eosinophils, and neutrophils were evoked by 1 nM, 100 nM, and 1 microM PAFacether, respectively, and by 30-100, 30-100, and 10 nM LTB4. The magnitude of the maximal chemotactic response to PAFacether of the densest eosinophils was significantly greater than that of neutrophils. The eosinophil responses to PAFacether were chemotactic, as distinguished from chemokinetic, and were not influenced by the percentage of contaminating neutrophils. PAFacether is a more potent chemotactic factor for eosinophils than neutrophils and selectively attracts the densest population of human blood eosinophils.

Chemotactic Factors, Eosinophil↗