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Biomedical subjects

H L Meier

Publications and source records attributed to H L Meier.

32 records · Page 2Linked to original sources
PubMed1984

In vivo model for the evaluation of topical antiallergic medications.

A novel human in vivo model of intranasal challenge with antigen is used to demonstrate the effectiveness of a topical antirelease drug. Previous experimentation has established a highly significant correlation between the physiologic response of sneezing, which occurs after insufflation of antigen into the nose of allergic individuals, and the recovery of putative mast cell mediators: histamine, tosyl arginine methyl ester (TAME)-esterase(s), and prostaglandin D2- Azatadine base, a tricyclic antihistamine, which also inhibits mediator release in vitro, applied prior to antigen administration not only reduces the clinical symptom of sneezing but simultaneously reduces the concentration of the inflammatory mediator, TAME-esterase(s), recovered from nasal washes. To our knowledge, this is the first observation that an antirelease drug can stop mediator release in vivo in the nose.

Administration, Intranasal↗
PubMed1984

An antigen-activated DFP-inhibitable enzyme controls basophil desensitization.

Diisopropyl fluorophosphate (DFP), an inhibitor of serine esterases, enhances IgE-mediated histamine release from human basophils and blocks the desensitization process (i.e., the antigen-induced hyporesponsiveness) in these cells. Both activities occur at relatively low concentrations of DFP (0.1 to 0.5 mM) and are dependent on an antigen-activated intracellular event: if DFP is removed before antigen addition, it has neither effect. Neither hydrolyzed DFP nor the non-phosphorylating diisopropyl methyl phosphate enhanced histamine release or blocked desensitization. In addition to providing a demonstrable biochemical correlate of desensitization, our data suggest that the desensitization process controls the release of mediators of allergic reactions.

Antigens↗
PubMed1984

Deuterium-oxide-induced histamine release from basophils of allergic subjects. I. Responsiveness to deuterium oxide requires an activation step.

Basophils from many atopic persons, and especially asthmatic patients, have been shown to release histamine in response to 44% deuterium oxide (D2O), whereas basophils from nonatopic persons do not release histamine. The present experiments analyzed the mechanisms by which D2O mediated release. It was found that although D2O induced release from washed leukocytes, it failed to induce release from whole blood or from leukocytes that had sedimented but had not been washed. The kinetics of release after washing were rapid and were equivalent regardless of the temperature at which cells were sedimented (O degrees or 37 degrees C). Washed cells became desensitized to the action of D2O within 30 to 60 min at 37 degrees C, whereas unwashed leukocytes did not become desensitized. Serum or plasma inhibited D2O-induced release, although high concentrations (1/5) were less inhibitory than lower ones (1/10 to 1/100). Basophils from D2O responders also released histamine in response to a "platelet enhancing factor" (PEF), whereas those from D2O nonresponders did not. As with D2O-mediated release, PEF-mediated release occurred only with washed leukocytes, desensitized within 30 to 60 min at 37 degrees C, and was inhibited by serum. These results suggest that D2O induces histamine release by augmenting the effects of an endogenous activation mechanism, and that PEF acts on the same (D2O-responsive) donors to augment this activation mechanism. Cell activation, as well as desensitization of this activation mechanism, occurs rapidly when basophils are washed free of plasma inhibitors and placed at 37 degrees C.

Asthma↗
PubMed1983

Mediator release after nasal airway challenge with allergen.

An in vivo model of human allergic disease has been developed in which nasal challenge with antigen leads to physiologic changes, together with a release of increased amounts of inflammatory mediators into nasal secretions obtained by washing the nose with saline. In 105 experiments involving 35 subjects, only allergic subjects consistently demonstrated an increase in the concentrations of the mast cell mediator, histamine, and the putative mast cell mediators, TAME-esterase and PGD2. The release of each mediator was significantly (p less than 0.001) related to the physiologic change (sneezing). The release of each mediator also correlated significantly with the release of the other 2 mediators (p less than 0.001). This system, for the first time, clearly relates an in vivo symptom and mediator release and thus should provide an excellent tool for the further study of the allergic response and nasal pathophysiology.

Adolescent↗
PubMed1983

Anaphylactic release of a prekallikrein activator from human lung in vitro.

We have demonstrated the in vitro IgE-mediated release of a prekallikrein activator from human lung. The lung prekallikrein activator was partially purified by sequential chromatography on sulfopropyl-Sephadex, DEAE-Sephacel, and Sepharose 6B. Purified human prekallikrein was converted to its active form (kallikrein) by the lung protease. The generated kallikrein was shown to be biologically active; that is, it generates bradykinin from purified human high-molecular weight kininogen and also cleaves benzoyl-propyl-phenyl-arginyl-p-nitroanilide, a known synthetic substrate of kallikrein. The lung prekallikrein activator differs from the known physiologic activators of prekallikrein (the activated forms of Hageman factor) with respect to: (a) size (it has a mol wt of approximately 175,000); (b) synthetic substrate specificity (D-propyl/phenyl/arginyl-p-nitroanilide is a substrate for the activated forms of Hageman factor, but not the lung protease); (c) antigenic specificity (an anti-Hageman factor immunoadsorbent column did not remove significant amounts of the lung protease, while it removed most of the activity of activated Hageman factor fragments); and (d) inhibition profile (the lung proteases was not inhibited by corn trypsin inhibitor). This prekallikrein activator provides a physiologic mechanism by which prekallikrein can be directly activated during IgE-mediated reactions of the lung. While the role of this lung prekallikrein activator in immediate hypersensitivity reactions and in other inflammatory processes is not clear, it does represent a first and important interface between IgE-mediated reactions and the Hageman factor-dependent pathways of the inflammatory response.

Anaphylaxis↗
PubMed1983

In vivo demonstration of inflammatory mediator release following nasal challenge with antigen.

An in vivo model system was developed to recover inflammatory mediators from the nose after antigen stimulation. In 105 experiments involving 35 subjects, antigen was introduced into the nose. Allergic individuals demonstrated an increase concentration of histamine, TAMe esterase and PgD2 during the physiologic changes of nasal obstruction and sneezing. Clinical symptoms and mediator release were highly correlated; moreover, the release of each mediator was significantly correlated to the others.

Airway Resistance↗
PubMed1980

Basophil mediators and their release, with emphasis on BK-A.

During IgE-mediated events, basophils secrete small molecular weight mediators (histamine, slow reacting substance, Eosinophil chemotactic factor) which are thought to participate in inflammatory processes. We here describe the IgE-mediated secretion of large molecular weight mediators which have the potential for the activation of the Hageman factor dependent pathways, and the generation of biologically active peptides. These large molecular weight basophil derived mediators may, through the activation of the Hageman factor dependent pathways, influence mechanisms which participate in both acute and chronic cell-mediated inflammatory processes. We suggest that these proteases may participate not only as mediators of the immediate hypersensitivity reaction, but may also function in important aspects of the entire inflammatory response.

Autacoids↗
PubMed1977

Activation and function of human Hageman factor. The role of high molecular weight kininogen and prekallikrein.

The activation and function of surface-bound Hageman factor in human plasma are dependent upon both high molecular weight (HMW) kininogen and prekallikrein. HMW kininogen does not affect the binding of Hageman factor to surfaces, but it enhances the function of surface-bound Hageman factor as assessed by its ability to activate prekallikrein and Factor XI. The initial conversion of prekallikrein to kallikrein by the surface-bound Hageman factor in the presence of HMW kininogen is followed by a rapid enzymatic activation of Hageman factor by kallikrein. The latter interaction is also facilitated by HMW kininogen. Kallikrein therefore functions as an activator of Hageman factor by a positive feedback mechanism and generates most of the activated Hageman factor during brief exposure of plasma to activating surfaces. HMW kininogen is a cofactor in the enzymatic activation of Hageman factor by kallikrein and it also augments the function of the activated Hageman factor generated. The stoichiometry of the Hagman factor interaction with HMW kininogen suggests that it enhances the activity of the active site of Hageman factor. Since HMW kininogen and prekallikrein circulate as a complex, HMW kininogen may also place the prekallikrein in an optimal position for its reciprocal interaction with Hageman factor to proceed. The surface appears to play a passive role upon which bound Hageman factor and the prekallikrein-HMW kininogen complex can interact.

Binding Sites↗
PubMedDate not supplied

Biochemical manipulation of intracellular glutathione levels influences cytotoxicity to isolated human lymphocytes by sulfur mustard.

Glutathione (GSH) is the major nonprotein thiol that can protect cells from damage due to electrophilic alkylating agents by forming conjugates with the agent. Sulfur mustard (HD) is an electrophilic alkylating agent that has potent mutagenic, carcinogenic, cytotoxic, and vesicant properties. Compounds that elevate or reduce intracellular levels of GSH may produce changes in cytotoxicity induced by sulfur mustard. Pretreatment of human peripheral blood lymphocytes (PBL) for 72 hr with 1 mM buthionine sulfoximine (BSO), which reduces intracellular GSH content to approximately 26% of control, appears to sensitize these in vitro cells to the cytotoxic effects of 10 microM HD but not to higher HD concentrations. Pretreatment of PBL for 48 hr with 10 mM N-acetyl cysteine (NAC), which elevates intracellular glutathione levels to 122% of control, appears to partially protect these in vitro cells from the cytotoxic effects of 10 microM HD but not to higher HD concentrations. Augmentation of intracellular levels of glutathione may provide partial protection against cytotoxicity of sulfur mustard.

Acetylcysteine↗
PubMedDate not supplied

Effects of specific inhibitors of cellular functions on sulfur mustard-induced cell death.

This study was conducted to determine whether inhibitors of normal cellular functions can reduce cytotoxicity induced by sulfur mustard (HD). The compounds examined include inhibitors of poly(ADP-ribose) polymerase (PADPRP), inhibitors of mono(ADP-ribose) transferase (MADPRT), inhibitors of lipid peroxidation, and an inhibitor of protein synthesis. To determine the effects of these compounds on HD-induced cell death, human lymphocyte preparations were treated with known concentrations (0.1 microM to 1000 microM) of an inhibitor and exposed to an estimated 87% effect concentration (EC87) of HD (170 microM) for loss in cell viability. Cell viability was determined at 24-26 hr post-exposure to HD using a dye (propidium iodide) exclusion assay and a flow cytometer. All of the selected PADPRP inhibitors were found to be effective at reducing the cytotoxic effects of HD. These inhibitors were rank-ordered based on the concentration that gives 50% (EC50) reduction of HD-induced cell death. A significant correlation (r = 0.94) was observed between the compounds' ability to inhibit PADPRP and the compounds' ability to reduce HD- induced cell death, suggesting that PADPRP plays a role in HD-induced cell death. Inhibitors of MADPRT, lipid peroxidation, and protein synthesis were not effective at reducing HD-induced cell death.

ADP Ribose Transferases↗
PubMedDate not supplied

Ultrastructural correlates of the protection afforded by niacinamide against sulfur mustard-induced cytotoxicity of human lymphocytes in vitro.

Sulfur mustard (HD) has been shown to cause a concentration-dependent decrease in viability of human lymphocytes in vitro as measured by dye exclusion; this decrease is preventable by inhibitors of poly(adenosine diphosphatase ribose) polymerase such as niacinamide. The present study investigates the morphologic correlates of the protection afforded by niacinamide through scanning and transmission electron microscopic analysis of human lymphocytes incubated in the presence or absence of 10(3) M niacinamide for 24 h at 37 degrees C and exposed in vitro to 10(-3) M HD. Lymphocytes exposed to HD alone demonstrated 30% to 40% viability and loss of microvilli, large cytoplasmic vacuoles, extensive blebbing of the perinuclear envelope, loss of cytoplasmic organelles, condensation of nuclear chromatin, and multiple perforations of the plasmalemma. In the presence of niacinamide HD-treated lymphocytes had a viability of 87% and, except for blunting of the microvilli, essentially normal ultrastructure. Although the sequence of observed ultrastructural changes was not established, results of this morphologic study suggest that, in addition to the prevention of plasmalemmal defects and dye infusion, the mechanism of niacinamide protection appears to include preservation of the morphologic and functional integrity of cellular organelles.

Cell Membrane↗