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Biomedical subjects

Z Marom

Publications and source records attributed to Z Marom.

52 records · Page 3Linked to original sources
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

Mast cells and asthma. The role of mast cell mediators in the pathogenesis of allergic asthma.

Upon a specific allergic reaction mediators released from mast cells found free in the bronchial lumen or in the epithelial surface loosen the interepithelial cell tight-junctions allowing the entrance of more allergen to deeper mast cells. The primary and secondary mediators thereby generated induce further increased vascular permeability which leads to the entrance of plasma proteins and platelets. The other immediate responses induced by mediator release are smooth muscle constriction, mucus secretion and leukocyte chemoattraction. Vagal afferent and reflex efferent stimulation are induced by histamine and probably other mediators which might contribute both to the bronchospasm as well as mucous gland secretion. Subacute responses include increased cellular infiltrates, mucosal edema, desquamation, basement membrane thickening, goblet cell hyperplasia and mucus secretion. These responses may occur because of the continued release of primary and secondary mediators as well as effects caused by the mast cell granule matrix-derived factors. It can thus be seen that many of the pathologic features of asthma may be attributed to mast cell degranulation.

Airway Obstruction↗
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↗
PubMed1981

Effects of arachidonic acid, monohydroxyeicosatetraenoic acid and prostaglandins on the release of mucous glycoproteins from human airways in vitro.

Human lung explants maintained in culture for 7 d incorporate [(3)H]glucosamine into mucous glycoproteins. Ethanol-precipitable, glucosamine-labeled mucous secretion was measured, and the effects of different pharmacologic agents upon this secretion were investigated. Anaphylaxed human lung generates prostaglandin (PG) synthesis and increased mucous release. Arachidonic acid (AA), PGA(2), PGD(2), and PGF(2alpha) significantly increased mucous glycoprotein release, whereas PGE(2) significantly reduced release. Evidence which suggests that lipoxygenase products of AA augment mucous release includes the following: (a) Nonsteroidal anti-inflammatory drugs (NSAID: acetylsalicylic acid and indomethacin) increase mucous release while preventing prostaglandin formation. (b) The increase in mucous release induced by AA or NSAID is additive once the agents are combined. (c) Several nonspecific lipoxygenase inhibitors (eicosa-5,8,11,14-tetraynoic acid; vitamin E; nordihydroguaiaretic acid; and alpha-naphthol) inhibit mucous release. Three additional lines of evidence directly indicate that monohydroxyeicosatetraenoic acid (HETE) causes increased mucous release: (a) the addition of a mixture of synthetic HETE (24-600 nM) increases mucous release; (b) pure 12-HETE (1-100 nM) also increases mucous release; (c) mucous release is increased synergistically by the combination of HETE and NSIAD. These data taken together demonstrate that HETE are capable of increasing mucous release and that conditions which may influence HETE production alter mucous release. Thus, although not directly demonstrating HETE production by human airways, the data strongly suggest that lipoxygenase products of AA in airways may profoundly influence mucous release; and it seems possible that lipoxygenase inhibitors may have a role in treating bronchorrhea.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1980

Immunologic and neuropharmacologic stimulation of mucous glycoprotein release from human airways in vitro.

Human bronchial airways obtained after surgical resection were maintained in tissue culture for 24-48 h. Incorporation of [(3)H]- or [(14)C]-glucosamine, [(14)C]threonine, or Na(2)[(35)S]O(4) to the culture media resulted in biosynthesis of two radiolabeled glycoproteins-one filtering in the exclusion volume of Sepharose 2B, and the other filtering with an approximate molecular weight of 400,000. Both fractions had similar elution patterns from DEAE-cellulose anion exchange chromatography. [(3)H]Glucosamine was incorporated equally into the two fractions. The effects of anaphylaxis, histamine, and several neurohormones upon the release of [(3)H]glucosamine-labeled glycoproteins were analyzed, making no attempt to separate the two glycoprotein fractions. Three lines of evidence were found suggesting that mast-cell degranulation increases mucous release from cultured airways. (a) Supernatant fluids from anaphylaxed peripheral human lung that contained 200-400 ng/ml histamine and 400-1,000 U/ml slow-reacting substance of anaphylaxis (SRS-A) increased release by 40+/-18%. (b) The addition of antigen to IgE-sensitized airways led to the release of 26+/-7% of the total histamine and a 36+/-14% increase in mucous release. (c) Reversed anaphylaxis with anti-IgE antibodies induced a 36+/-6% release of histamine from the airways and an increase in the release of mucous glycoproteins of 25+/-9%. Exogenous histamine added to airways increased mucous glycoprotein release, an effect prevented by cimetidine, an H-2 antagonist. Selective histamine H-2, but not H-1 agonists increased mucous glycoprotein release, suggesting the possibility that anaphylaxis of airways results in increased mucous glycoprotein release partly through histamine H-2 stimulation.A cholinomimetic agonist, methacholine, increased mucous release; this response was prevented by atropine which alone had no effect. No response to beta-adrenergic stimulation with either isoproterenol or epinephrine was noted. However, alpha-adrenergic stimulation with either norepinephrine combined with propranolol or phenylephrine alone resulted in dose-related increases in glycoprotein release. Both alpha-adrenergic and cholinergic stimulation of human tissues induce the formation of guanosine 3',5'-phosphoric acid (cyclic GMP), and 8-bromo cyclic GMP added to the airways led to increased mucous secretion. Thus, it seems likely that neurohormones capable of stimulating cyclic GMP formation in human airways may lead to increased mucous glycoprotein release.

Anaphylaxis↗
PubMed1980

Modulation of human monocyte functions by Fc fragments of IgG: a comparison to other monocyte 'activators'.

Human monocytes were maintained in tissue culture and the effect of various stimuli on their morphology and capacity to synthesize and secrete total protein, lysozyme, acid phosphatase, prostaglandin E and the second component of complement were determined. Human monomeric IgG, Fab fragments and albumin had no effect on the secretion of these products. However, addition of Fc fragments significantly decreased the synthesis of both lysosomal enzymes and the second component of complement and increased production of prostaglandin E. The addition of Con A to the monocyte monolayers resulted in a similar response. Latex particles slightly increased the secretion of acid phosphatase and C2, but had no effect on lysozyme secretion. Fc fragments also stimulated protein synthesis by monocyte monolayers cultured in serum-free medium. These 'activators' and endotoxin- or antigen-activated mononuclear cell supernatants (AMNS) resulted in varying degrees of increased spreading and adherence of the monocytes. The results of these studies suggest that the molecular species inducing the 'activated state' qualitatively and quantitatively determines the characteristics of the secretory response.

Acid Phosphatase↗
PubMedDate not supplied

Analysis of human nasal mucous glycoproteins.

Human nasal turbinates were cultured in the presence of 3H-glucosamine, which is incorporated into nasal mucous glycoproteins. Nasal mucous glycoprotein was then characterized biochemically, and the effects of various neurohormones and immunologic stimulation on mucous glycoprotein release were analyzed. Fractionation of nasal mucous glycoprotein by gel filtration chromatography revealed a molecular size range of 2 to 200 X 10(5) (as judged by protein markers) but displayed a single, acidic charge, as reflected both in a narrow elution pattern from DEAE-cellulose and a sharp isoelectric focusing point of 2.6. Highly enriched nasal mucous glycoprotein preparations consisted of 80 per cent carbohydrate and 20 per cent protein (by weight) and included enzymatically cleavable carbohydrate side chains with molecular weights of 1,600 to 1,800. Thus, nasal mucous glycoproteins are a family of molecules that express uniform acidic charge characteristics and a wide range of molecular sizes. Cholinergic stimulation of atropine-inhibitable muscarinic receptors increased nasal mucous glycoprotein release in a dose-related manner, as did alpha-adrenergic stimulation. However, beta-adrenergic stimulation did not affect mucous glycoprotein release. Immunologic stimulation of nasal mast cells by either reversed anaphylaxis or antigen challenge after passive sensitization caused both histamine release and increased mucous glycoprotein release. Thus, nasal turbinates provide an accessible source of tissue for the analysis of nasal mucus secretion and mast cell degranulation and may provide a model for the study of pharmacologic approaches to the universally experienced discomfort of rhinorrhea.

Antibodies, Anti-Idiotypic↗
PubMedDate not supplied

Goblet cell density of the inferior turbinates in patients with perennial allergic and nonallergic rhinitis.

Nasal mucus production is regulated by submucosal glands and epithelial goblet cells. The role and especially the number of the latter are quite debatable. The present study compares the distribution and density of goblet cells in the inferior turbinates of patients with perennial allergic and nonallergic rhinitis to normal controls. The periodic acid Schiff-alcian blue whole-mount method was used to identify and count their number. Goblet cell distribution was found nonhomogeneous, and considerable variations were observed among adjacent localities of the same specimen. The mean number of goblet cells per mm2 was 6499 in normal controls (n = 12), 6818 in patients with perennial allergic rhinitis (n = 13), and 6801 in patients with perennial nonallergic rhinitis (n = 18). Statistical analysis confirmed that the density of goblet cells did not differ significantly between patients with and without allergy, as well as between each group of patients and controls. Therefore, it could be concluded that the number of goblet cells in the inferior turbinate is not influenced by the presence of perennial allergic or nonallergic rhinitis.

Cell Count↗
PubMedDate not supplied

Inferior turbinate goblet cell secretion in patients with perennial allergic and nonallergic rhinitis.

Perennial rhinitis is clinically associated with a significant increase in nasal mucus secretion. Moreover, it has already been established that the number of goblet cells, in the inferior turbinates of patients with perennial allergic and nonallergic rhinitis, does not differ from that of normal subjects. Thus a question is raised, whether the above-mentioned phenomenon is ascribed exclusively to submucosal glandular activity, or may also be a result of a nonhyperplastic increase of goblet cell functional activity. This study was conducted to assess inferior turbinate goblet cell mucus secretion in a cohort of patients with perennial allergic and nonallergic rhinitis compared with normal controls. A semiquantitative morphometric method was used to examine goblet cell mucus secretion in sections stained with Alcian blue and periodic acid Schiff. Mucus secretion in each section was established in terms of secretory ratio, calculated as the number of secreting goblet cells divided by the number of nonsecreting ones. The mean secretory ratio of patients with perennial allergic (n = 11) and nonallergic rhinitis (n = 23) was 0.89 and 0.57, respectively, compared to controls (n = 10) 0.25. Statistical analysis confirmed that the secretory ratio of patients with perennial allergic rhinitis was significantly higher than that of the control group. No significant difference prevailed between patients with perennial nonallergic rhinitis and controls, as well as between allergic and nonallergic patients. Based on the results of the study, a basal state of nasal goblet cell mucus secretion in nonstimulated healthy people was established. Furthermore, it was concluded that the enhancement in mucus discharge, from the inferior turbinate goblet cells of patients with perennial allergic rhinitis, was attributed to a nonhyperplastic increase of nasal goblet cell functional activity.

Analysis of Variance↗
PubMedDate not supplied

Characterization of a unique mucin-like glycoprotein secreted by a human endometrial adenocarcinoma cell line (Ishikawa).

A human endometrial adenocarcinoma cell line (Ishikawa) has been shown to incorporate [3H]glucosamine and to secrete a radiolabeled high molecular weight compound which is excluded from a Sepharose CL-2B column. The excluded material was resistant to hyaluronidase, chondroitinase ABC, and heparinase. These findings rule out the possibility of this material being a proteoglycan. The susceptibility of this material to digestion with pronase, neuraminidase, and alkaline borohydride treatment strongly suggests that the excluded material is an O-glycosidic glycoprotein. The glycoprotein secreted by Ishikawa cells (ICGP) did not react immunologically with antibodies against either lactoferrin or fibronectin, but did react with an antibody made against tracheal mucin. Conversely, immunoblot analysis revealed that an antibody made against ICGP did not recognize hyaluronic acid, chondroitin, heparin, nasal turbinate mucin, bovine submaxillary gland mucin, lactoferrin, or fibronectin, but did recognize tracheal mucin. Analysis of ICGP amino acid and carbohydrate composition showed that it is rich in serine, threonine, glutamic acid, aspartic acid, and N-acetylneuraminic acid. In this respect, ICGP differs from other mucins, even though it is immunologically similar to respiratory mucin; hence we may consider ICGP to be a mucin-like glycoprotein. Secretion of ICGP can be modulated by Ca(2+)-ionophore and other mucus secretagogues, such as platelet activating factor, carbachol, and monocyte/macrophage mucus secretagogue, all mediators of lung inflammation. Ishikawa cells and anti-ICGP antibody may be used in studies on in vitro regulation of mucin-like glycoprotein synthesis and secretion in the respiratory tract as well as in the endometrium.

Adenocarcinoma↗
PubMedDate not supplied

Prognostic significance of p53 and ras p21 protein expression in surgically treated non-small cell lung carcinoma.

BACKGROUND AND OBJECTIVE: The prognosis of surgically treated non-small cell lung carcinoma (NSCLC) varies even after careful selection of the patients; the conventional grading and staging system is often deficient in determining which cases will profit best from surgery. Additional techniques are needed to permit better prognostic evaluation. METHODS: In this research, 2 markers of cellular proliferation, p53 and ras (p21) proteins were examined. The material used was from the same series reported previously which were immunostained with different cytokeratin markers for the same purpose. Immunohistochemical stainings of p53 and p21 were performed on the paraffin sections of 88 NSCLC specimens: 45 squamous cell, 22 adeno- and 21 large or undifferentiated carcinomas. RESULTS: At stage I, positive or negative stains of p53 and p21 provided no prognostic information since they had similar 5 year survival rates of approximatively 50% which is similar to the mean predicted survival rate for stage I. In this group as well, there was no significant difference in immunostaining, either in relation to the histological type or grade of the tumors. At stage III-IV, we found a trend, which, however, was not statistically significant, between positive immunostains of p53 and p21 proteins and longer survival. CONCLUSIONS: These results vary from our previous study on the expression of the differentiation marker cytokeratin 18, which showed that positive staining of tumor cells was associated with a statistically significant poorer prognosis at stage I regardless of histological types.

Aged↗