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Biomedical subjects

M Kaliner

Publications and source records attributed to M Kaliner.

At least 91 records · Page 5Linked to original sources
PubMed1983

The biologic activity of mast cell granules. V. The effects of antihistamine treatment on rat cutaneous early- and late-phase allergic reactions.

Mast cell-dependent late-phase allergic reactions (LPR) as sequelae of immediate hypersensitivity responses (IR) occur in both human and rat skin; thus the rat has served as a useful model to investigate the pathogenesis of cutaneous LPR. To analyze the roles that histamine might play in the generation of rat LPR, the effects of H1 and/or H2 antihistamines on both LPR and antecedent blueing responses (IR) were investigated. Systemically administered diphenhydramine and cimetidine, alone or in combination, reduced blueing reactions to histamine. However, blueing responses to anti-IgE were only partially abrogated by antihistamine treatment with diphenhydramine alone or the combination of antihistamines. Diphenhydramine treatment alone partially inhibited the histologic intensity of LPR in a dose-dependent manner. Although cimetidine treatment alone had no inhibitory effect, it potentiated the diphenhydramine-induced inhibition of LPR. The inhibitory action of antihistamine treatment was apparent only in reactions elicited by anti-IgE or mast cell granules containing histamine, since LPR caused by histamine-free mast cell granules were not affected by antihistamines. This observation suggests that the inhibitory effect of antihistamines on LPR was the result of a specific blockade of histamine receptors rather than the result of a nonspecific suppressive effect. Our findings demonstrate that cutaneous inflammation generated as a result of mast cell degranulation can be significantly reduced by treatment with H1 and H2 histamine receptor antagonists.

Animals↗
PubMed1983

Measurement of urinary histamine: comparison of fluorometric and radioisotopic-enzymatic assay procedures.

Assessment of urinary histamine may prove useful in determining the role of histamine in human health and disease. Urinary histamine may be accurately estimated by a modified fluorometric assay employing diamine oxidase (DAO) digestion and cation-exchange chromatography. Normal urine histamine values obtained by this assay are: arithmetic means (+/- SEM), 8.6 +/- 0.6 ng/ml and 10.5 +/- 0.7 micrograms/24 hr; geometric means (+/- SEM), 6.2 +/- 1.1 ng/ml and 10.0 +/- 1.3 micrograms/24 hr. However, the radioisotopic-enzymatic assay is less expensive, easier to perform, and possibly more sensitive. Therefore the two procedures were compared. The radioenzyme assay was found to be affected by factors in urine (possibly salt concentrations) requiring extraction of histamine from urine by butanol-heptane. Moreover, it was found to be necessary to compare DAO-digested samples with undigested samples to accurately estimate histamine levels and to run the standard curve of histamine in DAO-digested urine. Even with these modifications, the radioenzyme assay was not as accurate as the fluorometric assay for urine samples having histamine values about 60 ng/ml. Therefore we recommend utilization of the modified fluorometric assay for the measurement of urinary histamine levels.

Amine Oxidase (Copper-Containing)↗
PubMed1983

Abnormal beta-adrenergic responsiveness in allergic subjects. II. The role of selective beta 2-adrenergic hyporeactivity.

Isoproterenol increases systolic blood pressure by increasing cardiac output through beta 1-adrenergic stimulation and lowers diastolic pressure by reducing peripheral resistance, which is a beta 2-adrenergic response. It was therefore possible to compare beta 1 and beta 2 responsiveness of allergic subjects to determine whether asthmatics behaved differently than did rhinitis patients or even "preallergic" subjects, who have positive skin tests in the absence of symptoms. All the allergic subjects required significantly more isoproterenol to increase their pulse pressure 22 mm Hg or greater as compared with normal subjects. Analysis of the beta 1 and beta 2 components of the pulse pressure change revealed normal beta 1 responses (systolic increase) and abnormal beta 2 responses (diastolic decrease) in all allergic groups. Moreover, even at the point where the pulse pressure was driven to increase by 22 mm Hg or more, the allergic subjects had a reduced diastolic (beta 2) component. These studies demonstrate beta-adrenergic abnormalities in allergic subjects who were well controlled for concomitant drug administration, thereby extending and confirming the results of many earlier studies. In addition, this study extends the selective beta 2-adrenergic defect to all allergic subjects, not just asthmatics, as was suspected earlier.

Adrenergic beta-Agonists↗
PubMed1983

Human airway monohydroxyeicosatetraenoic acid generation and mucus release.

The effects of 5-, 8-, 9-, 11-, 12-, and 15-monohydroxyeicosatetraenoic acid (HETE) (0.1-100 nM) on mucous glycoprotein release from cultured human airways were determined. Each of the HETE was an active secretagogue of mucus at concentrations greater than 1-10 nM with 12- and 15-HETE, the most active. Both 5- and 9-hydroperoxyeicosatetraenoic acid (HPETE) were also active as secretagogues at 100 nM, although of somewhat lower potency. As cultured airways were capable of responding to HETE with mucous glycoprotein release, it was of interest to identify and quantitate airway HETE formation. Accordingly, airways were incubated with tracer quantities of [14C]arachidonate for 16-48 h, and the spontaneous formation of 5-, 12- and 11- and/or 15-HETE was measured by high-pressure liquid chromatography. Indeed, sizeable quantities of 11- and/or 15- greater than 5- greater than 12-HETE were generated. This HETE generation was increased by the addition of 25 micrograms/ml of arachidonate and was reduced somewhat after 18-21 d in continuous tissue culture. Reversed anaphylaxis of human airways using anti-human IgE markedly increased the HETE formation, resulting in the production of micromolar concentrations of 5- and 11- and/or 15-HETE. Thus, human airways not only are capable of responding to the presence of HETE with mucous glycoprotein release, but also generate (both spontaneously and in response to anaphylaxis) at least three species of HETE, and do so in quantities capable of acting as mucus secretagogues.

Anaphylaxis↗
PubMed1983

Possible mechanisms underlying mucus secretion in aspirin-sensitive asthma.

To study the hypersecretion of mucus in human airways, an in vitro model was developed. The effect of prostaglandins, nonsteroidal anti-inflammatory drugs, lipoxygenase products of arachidonic acid, and other mucus-stimulating and mucus-inhibiting agents was studied. The data suggest that arachidonic acid metabolized through its lipoxygenase pathway leads to the formation of potent stimulators of mucus release. Among them are the monohydroxyeicosatetraenoic acids, which are produced in large quantities by human airways, and the leukotrienes, which are generated during allergic reactions of the lung. As the lipoxygenase pathway is the only operant metabolic system available for arachidonic acid in the presence of aspirin and non-steroidal anti-inflammatory drugs--and as the nonsteroidal anti-inflammatory drugs themselves stimulate mucus production--it is possible that the mechanism responsible for mucus release in aspirin-sensitive asthmatics is the formation of these lipoxygenase products.

Aspirin↗
PubMed1983

The biologic activity of mast cell granules. IV. The effect of complement depletion on rat cutaneous late phase reactions.

Cutaneous late phase reactions (LPR) in rats can be induced by the intradermal injection of anti-IgE antibody or isolated rat peritoneal mast cell granules. Rat LPR are characterized by neutrophil-rich infiltrates at 2 to 8 hr followed by mononuclear cell-rich infiltrates thereafter. Rat Arthus reactions are histologically similar and are complement (C) dependent. To determine the importance of C in the pathogenesis of rat LPR compared with its role in Arthus reactions, rats were treated with cobra venom factor (CVF) (250 U/kg i.v.), and the effects of this treatment on total hemolytic complement (CH50), C3 titers, LPR, and Arthus reactions were assessed. CVF treatment produced profound decreases in both CH50 (from 197 +/- 20 to less than 1.0 U/ml) and C3 (from 44,240 +/- 2840 to less than 5 U/ml) titers after 6 hr, which persisted through at least 30 hr. The inflammatory intensity of heterologous reverse passive Arthus reactions was significantly decreased in CVF-treated animals. In contrast, the intensity of LPR was unaffected by CVF treatment. Therefore, although LPR and Arthus reactions share certain histologic characteristics, these similarities are not due to a mutual requirement for the presence of C.

Animals↗
PubMed1983

The biologic activity of mast cell granules. VI. The effect of vinblastine-induced neutropenia on rat cutaneous late phase reactions.

Type I immediate hypersensitivity reactions in human and rat skin may be followed by late phase reactions (LPR). A consistent feature of both human and rat LPR is the early histologic appearance of neutrophils, which, in rats, is followed by the later appearance (8 to 24 hr) of mononuclear cells. To determine the importance of the neutrophil in the development of LPR, rats were depleted of neutrophils using parenteral injections of vinblastine sulfate (VS). VS produced a dose-dependent neutropenia, with the maximal effect on day 4. LPR that were induced with anti-IgE, isolated mast cell granules (MCG), or purified high (greater than 10,000 daltons) and low (500 to 10,000 daltons) m.w. fractions obtained from MCG were significantly abrogated in VS-treated rats. In neutropenic rats previously immunized with complete Freund's adjuvant, the intensity of inflammatory reactions produced by skin testing with purified protein derivatives was also significantly reduced. Administration of exogenous neutrophils to neutropenic animals partially reconstituted the reduced LPR. These data confirm and extend previous observations on the contribution of neutrophils to delayed hypersensitivity reactions and provide evidence that the neutrophil is critical for the development of rat cutaneous LPR as well.

Agranulocytosis↗
PubMed1983

The biologic activity of mast cell granules. VII. The effect of anti-neutrophil antibody-induced neutropenia on rat cutaneous late phase reactions.

Mast cell-dependent late phase reactions (LPR) occur in rat skin and are characterized histologically by an early (1- to 8-hr) neutrophil-rich and later (8- to 24-hr) mononuclear cell-rich infiltrate. To extend previous observations on the role of the neutrophil in the sequential histologic development of cutaneous LPR, rats were selectively depleted of circulating neutrophils using rabbit anti-rat neutrophil antibody (anti-neut), and the effects of this treatment on the histologic intensity of LPR were analyzed. In addition, the effects of neutrophil depletion on cutaneous delayed-type hypersensitivity (DTH) reactions produced by immunization with Freund's complete adjuvant followed by intradermal challenge with purified protein derivative (PPD) were assessed. Following anti-neut treatment, cutaneous DTH reactions were unaffected. In contrast, selective neutrophil depletion resulted in significant reductions in the intensity of cutaneous LPR at both 6 to 8 and 24 hr following anti-IgE or rat mast cell granule injection. Further, statistical comparison of circulating neutrophil counts with the capacity of the animal to express LPR revealed a highly significant direct correlation. These data confirm the previous observations that rat LPR are neutrophil-dependent reactions.

Agranulocytosis↗
PubMed1982

A rapid method for isolation of human mononuclear cells free of significant platelet contamination.

In order to obtain mononuclear cells from peripheral human blood for the study of cell surface receptors, it was necessary to effectively eliminate contaminating platelets. The usual Hypaque-Ficoll isolation procedures were found to produce mononuclear cells contaminated with 10-1000 platelets per mononuclear cell (by phase microscopy). Multiple slow speed centrifugations reduced the contamination to 5-10 platelets per mononuclear cell. However, centrifugation of EDTA-anticoagulated blood through Hypaque (D20(20) 1.060) at 400 X g for 5 min at 22 degrees C followed by the usual Hypaque-Ficoll gradient reduced platelet contamination to less than 1 platelet per 2 mononuclear cells. Thus, a rapid and simple gradient procedure is capable of significantly reducing platelet contamination of mononuclear cell preparations and should facilitate the analysis of mononuclear cell receptors and functions.

Blood Platelets↗
PubMed1982

Histamine H-1 receptors on rat peritoneal mast cells.

In order to characterize the receptor subtype involved in histamine stimulation of increased cyclic AMP levels in rat mast cells with consequent impairment of anaphylactically induced mediator release, the binding of the H-1 receptor antagonist [3H]pyrilamine to mast cells was examined. Pyrilamine bound rapidly, in a saturable and reversible fashion, and with increased binding at 4 degrees C as compared with 21 degrees C and 37 degrees C. [3H]Pyrilamine binding was displaced by H-1 antagonists (tripelennamine greater than pyrilamine greater than or equal to diphenhydramine) greater than histamine greater than the H-2 antagonist, cimetidine. H-1 agonists displaced pyrilamine binding less efficiently than histamine but better than H-2 agonists. Rat mast cells have a single homogeneous population of low affinity (KD = 222 +/- 33 nM) H-1 receptors with a Bmax of 9.7 +/- 2.3 pm/10(6) mast cells and 5.4 +/- 0.92 x 10(6) binding sites per mast cell. Thus, the mast cell has an H-1 type histamine receptor which is probably involved in histamine-induced cyclic AMP increases.

Aminopyridines↗
PubMed1982

A characterization of beta-adrenergic receptors on cellular and perigranular membranes of rat peritoneal mast cells.

Beta-adrenergic receptors were characterized by measuring the specific binding of 3H-dihydroalprenolol (DHA) on intact isolated rat peritoneal mast cells (RPMC) and on perigranular membranes derived from purified RPMC granules. The specific binding of 3H-DHA reaches an equilibrium within 30 min at 5 degrees C and is linear with cell number. Scatchard analysis reveals two populations of binding sites on intact cells: with KD = 10.6 +/- 2.6 and 129 +/- 4.7 nM and Bmax of 186 +/- 38 and 1200 +/- 415 fmol/10(6) cells, respectively. Each cell contains 120 X 10(3) high-affinity binding sites and 720 X 10(3) low-affinity binding sites. There appears to be neither alpha-adrenergic nor muscarinic cholinergic receptors on the RPMC. Specific binding of 3H-DHA also occurred to isolated granules with perigranular membranes. The binding was saturable with a single population of binding sites with an affinity (KD) of 7.0 +/- 0.45 nM. Maximum binding (Bmax) was calculated at 56.6 +/- 1.9 fmol/10(9) granules. Subfractionation of granule components demonstrated that the specific binding sites appear to be localized exclusively on the perigranular membrane.

Animals↗
PubMed1982

Anthracycline-induced histamine release from rat mast cells.

Comparisons were made of the ability of doxorubicin, daunorubicin, rubidazone and aclacinomycin A to release histamine from rat peritoneal mast cells. Preliminary in vitro experiments indicated that doxorubicin (10(-6) to 2.5 X 10(-4) M), in contrast to compound 48/80 and the calcium ionophore A23187, did not produce significant release under any condition tested when purified or unpurified rat mast cells were used. In in vitro experiments, released histamine was measured in the cell-free supernatant of peritoneal fluid of rats after intraperitoneal injection of the agents. The time course of doxorubicin-induced histamine release from the peritoneum was rapid, with maximal release occurring within 4 to 6 min. Dose-response curves of the 4 agents over the range 10(-5) to 3.3 X 10(-3) M revealed that all caused histamine release, with 10(-3) M concentrations of each causing maximal release of comparable magnitude to that produced by 9.5 X 10(-6) M A23187. Treated mast cells recovered from the peritoneal cavity showed degranulation and vacuolization when examined by electron microscopy. Increased vascular permeability by the Evans-blue test was also noted with all 4 agents, and zones were of comparable size after injection of the highest concentration of each agent. The results indicate that in vivo, doxorubicin, daunorubicin, rubidazone and aclacinomycin A cause a rapid release of histamine from rat mast cells and an increase in vascular permeability in rat sin. There also appeared to be a reasonable correlation between the blueing reaction and histamine release in the peritoneal cavity in that the doses that did not cause skin blueing also failed to cause histamine release. The lack of histamine release by doxorubicin from mast cell preparations in vitro suggests that alterations to the doxorubicin molecule or the presence of other critical substances may be necessary for this activity to commence.

Aclarubicin↗
PubMed1982

Measurement of plasma histamine: description of an improved method and normal values.

The single isotopic-enzymatic assay of histamine was modified to increase its sensitivity and to facilitate measurement of plasma histamine levels. The modification involved extracting 3H-1-methylhistamine (generated by the enzyme N-methyltransferase acting on histamine in the presence of S-[methyl-3H]-adenosyl-L-methionine) into chloroform and isolating the 3H-1-methylhistamine by thin-layer chromatography (TLC). The TLC was developed in acetone:ammonium hydroxide (95:10), and the methylhistamine spot (Rf = 0.50) was identified with an o-phthalaldehyde spray, scraped from the plate, and assayed in a scintillation counter. The assay in plasma demonstrated a linear relationship from 200 to 5000 pg histamine/ml. Plasma always had higher readings than buffer, and dialysis of plasma returned these values to the same level as buffer, suggesting that the baseline elevations might be attributable to histamine. However, all histamine standard curves were run in dialyzed plasma to negate any additional influences plasma might exert on the assay. The arithmetic mean (+/- SEM) in normal plasma histamine was 318.4 +/- 25 pg/ml (n = 51), and the geometric mean was 280 +/- 35 pg/ml. Plasma histamine was significantly elevated by infusion of histamine at 0.05 to 1.0 micrograms/kg/min or by cold immersion of the hand of a cold-urticaria patient. Therefore this modified isotopic-enzymatic assay of histamine is extremely sensitive, capable of measuring fluctuations in plasma histamine levels within the normal range, and potentially useful in analysis of the role histamine plays in human physiology.

Chromatography, Thin Layer↗
PubMed1982

Effects of infused histamine: correlation of plasma histamine levels and symptoms.

Plasma and urine histamine levels were measured during sequential infusions of histamine (0.05, 0.1, 0.25, 0.5, and 1.0 microgram/kg/min histamine base for 30 min each) to determine the plasma level required to elicit flushing, headaches, tachycardia, and diastolic hypotension. Each study was performed with subjects on no medications or after pretreatment with hydroxyzine and/or cimetidine in order to confirm the receptor subtype involved in each of the responses. Resting plasma histamine levels were 0.62 +/- 0.12 ng/ml, and levels rose progressively indirect proportion to the concentration of infused histamine. Plasma levels of histamine required to elicit symptoms were as follows: 1.61 +/- 0.30 ng/ml = 30% increase in heart rate, 2.39 +/- 0.52 ng/ml = significant flush and headache, and 2.45 +/- 0.13 ng/ml = 30% increase in pulse pressure. Cimetidine pretreatment failed to influence the histamine level required to elicit symptoms, hydroxyzine pretreatment significantly raised the level required to increase heart rat by 30%, and the combination of antihistamines significantly raised the threshold for histamine to elicit all the response. Urine histamine was increased in direct proportion to the histamine infusions, and because of stability, accessibility, and the capacity for retrospective diagnosis, urine is the suggested fluid to employ to measure histamine release in humans.

Adult↗
PubMed1982

Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro.

Allergic pulmonary reactions in vivo lead to airway constriction and mucous secretion, whereas in vitro lung anaphylaxis lead to mediator release and increased mucous glycoprotein secretion from cultured human airways. Using quantitation of radiolabeled mucous glycoprotein from cultured airways as a model for mucous release, the effects of two leukotrienes, LTC4 and LTD4, were assessed. BOth biosynthetic and synthetic LTC4 and LTD4 produced dose-related increases in mucous production at concentrations of 1 to 1,000 units/ml (20 to 20,000 pg [LTD4] and 24 to 24,000 pg [LTC4]/ml). These enhancing actions were seen in 11 of 11 lung cultures, and were significantly prevented by the specific SRS-A antagonist FPL 55712. Therefore, LTC4 and LTD4, two major components of the allergic mediator SRS-A, are potent mucous secretagogues and may possibly contribute to the mucous secretion observed during allergic reactions in vitro and in vivo.

Asthma↗
PubMed1982

Autonomic nervous system abnormalities and allergy.

Abnormal autonomic nervous system responsiveness may contribute to the pathogenesis of asthma and other allergic diseases. Therefore, we measured alpha- and beta-adrenergic and cholinergic responsiveness in allergic subjects. Allergic asthmatic subjects had an abnormal adrenergic (alpha = hyperresponsive; beta = hyporesponsive) and cholinergic (hyperresponsive) profile. However, subjects with allergic rhinitis and preallergic subjects (those with positive allergen skin tests without any disease manifestation) had equivalent beta-adrenergic and cholinergic abnormalities. Thus, all allergic subjects showed abnormal beta-adrenergic hyporeactivity and cholinergic hypersensitivity whereas allergic asthma was singularly associated with excessive alpha-adrenergic responsiveness. Autoantibodies against beta-receptors were found predominantly in subjects with beta-adrenergic hyporeactivity. The presence of these autoantibodies and the physiologic abnormalities associated with their presence suggests a causitive relationship.

Adult↗