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Biomedical subjects

M A Kaliner

Publications and source records attributed to M A Kaliner.

At least 19 recordsLinked to original sources
PubMed1992

Phospholipase C-gamma 1 is translocated to the membrane of rat basophilic leukemia cells in response to aggregation of IgE receptors.

Aggregation of the high affinity receptor for IgE (Fc epsilon RI) on the surface of mast cells results in the rapid hydrolysis of membrane inositol phospholipids by phospholipase C (PLC). Although at least seven isoenzymes of PLC have been characterized in different mammalian cells, the isoenzyme involved in Fc epsilon RI-mediated signal transduction and the mechanism of its activation have not been demonstrated. We now report that PLC-gamma 1 is translocated to the membrane of mast cells after aggregation of Fc epsilon RI. Activation of rat basophilic leukemia cells, a rat mast cell line, with oligomeric IgE resulted in an increase in PLC activity in washed membrane preparations in a cell free assay containing exogenous [3H]phosphatidylinositol (PI). The increase in PLC activity has the same dose-response to oligomeric IgE as receptor mediated hydrolysis of inositol lipids (PI hydrolysis) in intact cells. Analysis by Western blot probed with anti-PLC-gamma 1 antibody revealed that there is a three- to fourfold increase in PLC-gamma 1 in membranes from activated cells. The increase in PLC activity is augmented a further 20% by the addition of orthovanadate to the incubation medium suggesting that a tyrosine phosphatase is involved in the down-regulation of this phenomenon. These findings demonstrate translocation of PLC-gamma 1 to the membrane following activation of a receptor which does not contain intrinsic tyrosine kinase activity. Activation of PLC-gamma 1 by this pathway may account for Fc epsilon RI-mediated PI hydrolysis.

Animals↗
PubMed1992

Effects of in vivo administration of interleukin-2 (IL-2) and IL-4, alone and in combination, on ex vivo human basophil histamine release.

Human basophils possess receptors for interleukin-2 (IL-2) and IL-4. The effect of 3 days of intravenous administration of IL-2 and/or IL-4 on basophil histamine release was examined in three groups of patients receiving IL-2, IL-4, or the combination of agents as part of a protocol to treat malignant melanoma or renal cell carcinoma. Because all patients received ranitidine for control of side effects, a control group of patients receiving ranitidine for Zollinger-Ellison's syndrome was also studied. IL-4 significantly inhibited IgE-mediated histamine release, while there was a trend for enhancement of IgE-mediated histamine release by IL-2. Administration of the combination of IL-2 and IL-4 did not alter IgE-mediated basophil histamine release. Both IL-2 and IL-4, alone and in combination, enhanced basophil histamine release induced by histamine releasing factors in human nasal washings. The effect of IL-2 alone was significantly greater than that of IL-4 alone or the combination of IL-2 plus IL-4. Taken together, the data suggest that when coadministered, IL-4 may inhibit the effects of IL-2 on basophils. Neither cytokine exerted any effect on basophil histamine release induced by the calcium ionophore A23187, nor did ranitidine cause any effects on histamine release induced by any of the stimulants. Thus, human basophil reactivity can be affected by IL-2 and by IL-4. The role that these two cytokines play in basophil function in vivo is likely to be complex.

Adult↗
PubMed1992

The effect of IL-4 on human nasal mucosal responses.

Interleukin (IL)-4 causes the dose limiting sensation of nasal congestion when administered systematically at doses of 3 micrograms/kg or higher thrice daily to humans. This side effect was observed in a group of patients treated as part of an immunotherapy protocol for cancer management. To determine the source of this congestion, nasal secretions were collected prospectively in a group of patients at baseline and after provocation with normal saline, methacholine (which stimulates glandular secretion), and histamine (which causes increased vascular permeability). Nasal lavages obtained at baseline and after provocation were analyzed for the presence of these glandular and vascular proteins and inflammatory mediators. Washings and provocations were performed before IL-4 administration, after 24 hours of IL-4 treatment, and after 3 days of treatment, at a time when nasal congestion was maximal. Compared with histamine challenge before IL-4 treatment, the secretion of the plasma proteins albumin and IgG were significantly decreased after 3 days of IL-4 treatment. IL-4 treatment had no apparent effect on methacholine-induced responses. Thus systemically administered IL-4 causes the subjective sensation of nasal congestion, increased histamine in nasal lavages, and the development of vascular unresponsiveness to histamine, without affecting parasympathetic responses to histamine. The relationships among increases in nasal lavage histamine, vascular unresponsiveness to histamine, and the sensation of nasal congestion are unclear.

Adult↗
PubMed1992

Mediators of allergic rhinitis.

Although histamine is the principal mediator of the immediate allergic reaction, other inflammatory mediators as well as neuropeptides also contribute to rhinorrhea and nasal congestion. Within minutes of exposure to allergen, mast cells produce histamine, leukotriene C4, and prostaglandin D2. A concomitant increase occurs in neuropeptides and bradykinin. In vitro mast cell activation also leads to the release of tumor necrosis factor--alpha, several interleukins, and granulocyte-macrophage colony--stimulating factor. Because all these various mediators and neuropeptides may play a role in producing rhinorrhea and congestion, antihistamines alone cannot control all of the symptoms of allergic rhinitis. However, the combination of antihistamines with topical corticosteroids can inhibit the generation, release, and activity of most if not all of the mediators potentially involved in the allergic response.

Histamine↗
PubMed1992

Human nasal host defense and sinusitis.

Sinusitis is an exceptionally common disorder that affects an estimated 35 million Americans per year. The development of sinusitis requires both the presence of a virulent pathogen and the failure of the local immune system to prevent or effectively combat the infection. Identification of the components of the immune defense system of the upper respiratory tract and the possible areas of dysfunction that predispose to sinusitis may be important steps in the eventual prevention of this common disease. The nasal and sinus passages are lined by respiratory mucous membranes. Recent studies have identified some of the constituents found in mucus and their roles in human health and disease. However, the local immune system of the respiratory mucosa is largely unknown, and its role in sinusitis is conjectural. Nasal secretions include many proteins that serve important functions in local mucosal host defense. Most of these host-defense molecules are synthesized and secreted by serous cells in the submucous glands, and it appears that the serous cell is the resident antimicrobial cell in mucous membranes. Currently data suggest that serous cell secretion is abnormal in patients with recurrent sinusitis and that effective treatment leads to correction of the secretory abnormality along with improvement in sinusitis.

Humans↗
PubMed1992

Ibuprofen augments bradykinin-induced glycoconjugate secretion by human nasal mucosa in vivo.

Bradykinin (BK) stimulates vascular permeability and glycoconjugate secretion in human nasal mucosa. Since some of the effects of BK may be mediated by autocrine generation of arachidonic acid metabolites, the influence of ibuprofen, a cyclooxygenase inhibitor, on BK-induced nasal secretion was studied. Six normal male subjects had nasal provocations with 0, 10, 100, and 1000 nmol of BK before and after treatment with 400 mg of ibuprofen. Secretions were collected by nasal lavage. Total protein (marker of protein secretion), glycoconjugate (mucous cell marker), lysozyme (serous cell marker), and albumin (marker of vascular permeability) were measured. Basal glycoconjugate secretion was higher after ibuprofen (219 +/- 32 micrograms/ml) than before (81 +/- 56 micrograms/ml; p less than 0.05 by analysis of variance). BK stimulated significant, dose-dependent albumin, total protein, and glycoconjugate secretion. Lysozyme secretion was not stimulated. BK (1000 nmol) significantly increased total protein secretion, tenfold to twentyfold, and albumin secretion by 40-fold to 60-fold. Ibuprofen did not alter BK-induced total protein or albumin secretion. Glycoconjugate secretion after ibuprofen treatment was significantly higher than normal at 10 nmol (p less than 0.05), 100 nmol (p less than 0.02), and 1000 nmol of BK (519 micrograms/ml +/- 74 versus 213 +/- 15 micrograms/ml; p less than 0.05). Therefore, BK induces vascular permeability and exocytosis from glycoconjugate-containing cells but does not stimulate serous cells. Ibuprofen increases baseline secretion of glycoconjugate and enhances BK-induced glycoconjugate secretion. Ibuprofen does not alter BK-induced vascular permeability.

Adult↗
PubMed1992

Human neutrophil-derived histamine-releasing activity (HRA-N) causes the release of serotonin but not arachidonic acid metabolites from rat basophilic leukemia cells.

The effects of neutrophil-derived histamine-releasing activity (HRA-N) on arachidonic acid (AA) metabolism is unknown. Human basophils exposed to HRA-N released 25% of total histamine but no leukotriene C4 (LTC4). To confirm this phenomenon, rat basophilic leukemia (RBL) cells were exposed to HRA-N as well as anti-IgE, or calcium ionophore A23187. RBL cells incubated with A23187 released 44% of available serotonin and 59 and 124 pmol/10(6) cells of prostaglandin D2 (PGD2) and LTC4, respectively. Anti-IgE stimulation resulted in 34% serotonin release and the generation of 34 pmol PGD2 per 10(6) cells and 72 pmol LTC4 per 10(6) cells. In contrast, HRA-N (2 U/ml) induced 20% serotonin release, 4 pmol PGD2 per 10(6) cells, and 0.6 pmol LTC4 per 10(6) cells. Neither increasing the dose nor the incubation time of HRA-N enhanced the generation of AA metabolite. Additionally, the spectrum of AA metabolites generated by RBL cells in response to those agents was examined by reverse-phase high-performance liquid chromatography. RBL cells stimulated with A23187 released PGD2, LTB4, and its isomers, LTC4, and 5-hydroxyeicosatetraenoic acid. In contrast, HRA-N stimulation resulted in only minimal PGD2 generation and no other discernable AA metabolites. Thus, HRA-N causes selective release of serotonin without inducing AA metabolites. These data suggest that HRA-N activates mast cells through a unique pathway.

Animals↗
PubMed1992

Characterization and autoradiographic localization of histamine H1 receptors in human nasal turbinates.

To examine the localization of histamine H1 receptors (H1R) in human nasal mucosa, the autoradiographic distribution of H1R was studied in human nasal inferior turbinates. Cryostat sections were incubated with various concentration of [3H]pyrilamine in saturation-binding studies and with 1 nmol/L of [3H]pyrilamine for autoradiography. Nonspecific binding was determined by adding 2 mumol/L of pyrilamine. Scatchard analysis demonstrated high-affinity binding sites with a maximum binding capacity of H1R of 193 +/- 46 fmol/mg of protein, and dissociation constant was 0.6 +/- 0.1 nmol/L. Autoradiograms indicated H1R exist exclusively on the endothelium of vessels. No specific labeling could be observed in the submucosal glands or epithelium. These results extend and support our previous finding that histamine directly causes vascular permeability through H1R and stimulates nasal glandular secretion indirectly through reflexes.

Autoradiography↗
PubMed1992

Comparison of human nasal mucosal secretion in vivo and in vitro.

The secretion of proteins from the human nasal mucosa induced by histamine, alpha-adrenergic, beta-adrenergic, and cholinergic agonists was studied in vivo and in vitro. Glandular secretion of lactoferrin, lysozyme (in vivo only), and respiratory glycoconjugates (RGCs) was measured. Vascular permeability was determined in vivo by albumin secretion in relationship to the other proteins. Muscarinic stimulation by methacholine induced significant glandular secretion (lactoferrin, lysozyme and/or RCGs) both in vivo and in vitro, confirming that muscarinic receptors are stimulated directly. Histamine induced predominantly vascular permeability in vivo but caused some glandular secretion as well. However, in vitro, histamine had no effect on glandular secretion, suggesting that histamine acts predominantly on the nasal vascular bed and only affects glandular secretion through reflex actions. Phenylephrine, an alpha-adrenergic agonist, selectively stimulated lysozyme release in vivo, and both RGCs and lactoferrin release in vitro. Thus, alpha-adrenergic stimulation has some direct, albeit minimal, capacity to stimulate mucosal glands. beta-Adrenergic agonists had no effect on glandular secretion or vascular permeability either in vivo or in vitro. Therefore, glandular secretion is directly stimulated by alpha-adrenergic and cholinergic agonists, but not by beta-adrenergic agonists. The stimulation of glandular secretion by histamine is indirect and mediated through the action of neural reflexes.

Adult↗
PubMed1992

Effects of nedocromil sodium on allergen-induced rhinitis in humans.

Sixteen patients with allergic rhinitis were recruited into a double-blind crossover protocol studying the immediate effect of nedocromil sodium (NS) on the pattern of nasal symptoms and secretions after allergen challenge. After pretreatment with placebo or NS, allergen challenge resulted in pruritus, rhinorrhea, nasal congestion, and/or sneezing within 10 minutes in 12 of 16 subjects. Prostaglandin D2 (PGD2), a marker of mast cell degranulation, increased proportionately with symptom scores, remaining above the 95% confidence interval for 120 minutes after both pretreatments. No difference in PGD2 between the NS-treatment and placebo-treatment days was observed. Protein markers extravasated through the vasculature (albumin and IgG) or secreted by mucosal glands (lactoferrin) were assayed. Total protein, albumin, IgG, and lactoferrin all remained greater than 95% confidence interval for 100 minutes after allergen challenge in the placebo-pretreated group and 120 minutes in the NS-pretreated group. Although there appeared to be a trend for lower secretion of PGD2, albumin, and IgG in the NS-treated group, the overall differences did not achieve statistical significance. This protocol revealed that two topical 130 microliter doses of a 1% solution of NS failed to significantly reduce allergen-induced symptoms, PGD2 generation, or secretion of albumin, IgG, or lactoferrin when NS was compared with placebo. The anti-inflammatory and mast cell-stabilizing effects of NS may require more prolonged pretreatment before provocation to be effective.

Adult↗
PubMed1992

The effects of neuropeptides on mucous glycoprotein secretion from human nasal mucosa in vitro.

The role of neuropeptides in the regulation of macromolecule secretion from human nasal mucosa is incompletely understood. Previous in vitro explant culture studies have demonstrated the effects of neuropeptides on lactoferrin release from serous cells and 3H-glucosamine labeled respiratory glycoconjugate secretion from mucus-containing cells. The generation of a new monoclonal antibody, 7F10, has led to the development of an ELISA for high molecular weight respiratory mucous glycoproteins (MGP). This ELISA was used to measure the ability of sensory, parasympathetic and sympathetic neuropeptides to stimulate MGP release from human nasal mucosal fragments in short term explant culture in vitro. Significant MGP release was stimulated by the sensory neuropeptides gastrin releasing peptide (10 microM GRP: 10.6% +/- 2.4% increase, n = 8, P less than 0.01 vs. control), substance P (1 microM SP: 12.5% +/- 5.4%, n = 11, P less than 0.05), neurokinin A (1 microM NKA: 17.8 +/- 4.3%, n = 6, P less than 0.01), while calcitonin gene related peptide (CGRP) was without effect. Vasoactive intestinal peptide (VIP), a neurotransmitter from parasympathetic nerves, induced significant dose dependent MGP secretion, but had no additive or inhibitory interaction with methacholine-induced secretion. Neuropeptide Y (NPY), present in sympathetic nerves, had no effect on MGP secretion. These observations correlate with the effects of neuropeptides on serous cell lactoferrin secretion, and the presence of specific GRP, SP, and VIP binding sites on human nasal submucosal glands that have been detected by autoradiography. GRP and tachykinins (SP and NKA) from sensory nerves, and VIP released during parasympathetic reflexes may significantly stimulate mucous and serous cell secretion from human nasal mucosa in vivo.

Calcitonin Gene-Related Peptide↗
PubMed1992

Gastrin releasing peptide (GRP) binding sites in human bronchi.

The autoradiographic binding site of gastrin releasing peptide (GRP), the 27 amino acid mammalian form of bombesin, were examined in human bronchial mucosa. 125I-GRP bound specifically to submucosal glands and the epithelium. There was limited binding to vessels and bronchial smooth muscle. These observations suggest that GRP or GRP immunoreactive peptides which are present in nerve fibres and pulmonary neuroendocrine cells, may act upon glandular GRP receptors to induce mucus secretion, but that GRP would probably have little effect on vascular permeability or tracheobronchial smooth muscle tone.

Binding Sites↗
PubMed1992

Lactoferrin and lysozyme deficiency in airway secretions: association with the development of bronchopulmonary dysplasia.

To test whether the presence of airway inflammatory markers differentiated babies with hyaline membrane disease (HMD) who recovered (n = 18) from those in whom bronchopulmonary dysplasia (BPD) developed (n = 18), tracheal aspirate samples from 36 newborn infants with HMD who underwent intubation were collected during days 1 to 28 of life and analyzed for the mucosal antimicrobial proteins lactoferrin and lysozyme. For babies with HMD in whom BPD developed, lactoferrin concentrations were decreased during the first 4 days of life (7 +/- 3, 14 +/- 3, 18 +/- 3, and 18 +/- 3 micrograms/ml, respectively) in comparison with those in babies with HMD who recovered (23 +/- 8, 29 +/- 6, 41 +/- 9, and 81 +/- 19 micrograms/ml); group differences reached statistical significance on days 3 and 4 (p less than 0.05). Lysozyme levels in the secretions of babies with BPD were also lower on day 3 (31 +/- 5 micrograms/ml) than in those of babies who recovered (54 +/- 7.5 micrograms/ml). For babies with BPD whose endotracheal tube remained in place beyond day 4, lysozyme levels on days 5 to 12 were significantly lower for those classified as having severe BPD than for those with mild to moderate BPD. Because lysozyme and lactoferrin are products of serous cells found in submucous glands, it seems possible that the relative immaturity of submucous glands may influence the development of BPD.

Bronchopulmonary Dysplasia↗
PubMed1992

Anaphylaxis.

The syndrome of anaphylaxis is a life-threatening event in which the potential for patient morbidity and mortality is high. An understanding of the pathophysiology of anaphylaxis, the most serious of the allergic disorders, is paramount for its diagnosis. In addition to these elements, this article discusses newly recognized causes of anaphylaxis and reviews its treatment.

Anaphylaxis↗
PubMed1992

Bombesin stimulates human nasal mucous and serous cell secretion in vivo.

Bombesin, gastrin-related peptide (GRP), and related peptides sharing the common carboxyterminal sequence stimulate lactoferrin (serous cell marker) and glycoconjugate (mucous cell and goblet cell marker) release from human nasal mucosal explants in vitro. In vivo, GRP released from trigeminal sensory nerves may act upon GRP-bombesin binding sites on respiratory epithelial cells and submucosal glands. To determine whether GRP-bombesin can stimulate nasal secretion in vivo, bombesin was administered to eight normal subjects by unilateral, topical administration. Secretions from both nostrils were collected for measurement of total protein, lysozyme, hexose-containing glycoconjugates, and albumin (marker of vascular permeability). Baseline secretions contained 72.0 +/- 17.3 micrograms/ml of total protein, 14 +/- 2 micrograms/ml of lysozyme, 113 +/- 44 micrograms/ml of hexose-containing glycoconjugates, and 7.8 +/- 3.4 micrograms/ml of albumin. Hexose-containing glycoconjugate secretion was significantly increased after 1 nmol (385 +/- 63 micrograms/ml, P less than 0.001 by analysis of variance), 10, 100, and 1,000 nmol of bombesin, but the secretion was not dose dependent. Significant lysozyme (24 +/- 3 micrograms/ml, P less than 0.05) and total protein (155 +/- 23 micrograms/ml, P less than 0.01) secretion occurred after 1,000 nmol. No statistically significant changes in albumin secretion occurred at any dose. Saline had no significant effects on secretion. Therefore, bombesin stimulated secretion from submucosal glands and possibly epithelial cells in the human nose without affecting vascular permeability.

Adult↗
PubMed1992

Neuropeptide Y is a vasoconstrictor in human nasal mucosa.

Neuropeptide Y (NPY) is a neurotransmitter in sympathetic nerve fibers in human nasal mucosa. Like norepinephrine, NPY acts as a vasoconstrictor. An established method of nasal provocation was used to determine the effects of topically applied NPY on nasal resistance to airflow measured by anterior rhinomanometry, the protein content of nasal secretions, and the protein content of bradykinin-induced secretions. NPY (2.3 nmol) reduced the resistance to inspiratory airflow by 57 +/- 18% (P < 0.001) in 10 normal subjects and by 50 +/- 17% (P < 0.05) in 12 subjects with perennial rhinitis. In nasal provocations, NPY in doses of 0.1-10 nmol had no effect on vascular (albumin), glandular (lysozyme, glycoconjugate), or total proteins present in lavaged nasal secretions. Because the vasoconstrictor properties of NPY may only be apparent in the presence of increased vascular permeability and albumin exudation, bradykinin (BK) nasal provocation was performed. BK (500 nmol) significantly increase total protein (10- to 20-fold), albumin (10- to 30-fold), and glycoconjugate (2- to 5-fold) in lavage fluid. NPY (2.3 nmol) reduced BK-induced total protein by 59 +/- 15% (P < 0.05) and albumin by 63 +/- 17% (P < 0.02) but had no significant effect on glandular secretion. Therefore exogenous administration of NPY to the human nasal mucosa reduced nasal airflow resistance and albumin exudation without affecting submucosal gland secretion. NPY agonists may be useful for the treatment of mucosal diseases characterized by vasodilation, vascular permeability, and plasma exudation.

Adult↗
PubMed1992

M1 and M3 muscarinic antagonists inhibit human nasal glandular secretion in vitro.

Mucus glycoproteins (MGP) are high-molecular-weight glycoconjugates that are released from submucosal glands and epithelial goblet cells in the respiratory tract. Muscarinic receptors have an important role in the regulation of human nasal glandular secretion and mucus production, but it is not known which of the five muscarinic receptor subtypes are involved. The effect of nonselective and M1-, M2-, and M3-selective muscarinic antagonists on methacholine (MCh)-induced MGP secretion from human nasal mucosal explants was tested in vitro. MGP was assayed by enzyme-linked immunosorbent assay using a specific anti-MGP monoclonal antibody (7F10). MCh (100 microM) induced MGP secretion up to 127% compared with controls. MCh-induced MGP release was significantly inhibited by atropine (100 microM), the M, receptor antagonist pirenzepine (10-100 microM), and the M3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; 1-100 microM). 4-DAMP significantly inhibited MCh-induced MGP release at a lower concentration (1 microM) than pirenzepine (10 microM). The M2 receptor antagonists AF-DX 116 and gallamine (both at 100 microM) had no effect. No antagonist alone had a significant effect on MGP release. These results indicate that the M1 and M3 muscarinic receptor subtypes regulate MGP secretion from human nasal mucosa and suggest that the M3 receptor has the predominant effect.

Antibodies, Monoclonal↗