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Biomedical subjects

W M Gold

Publications and source records attributed to W M Gold.

At least 55 records · Page 3Linked to original sources
PubMed1986

Mechanisms of antigen-induced reactions in skin and lung.

Investigators have tried to develop various experimental preparations suitable to study the effects of antigen on skin and airways in order to understand the mechanisms involved in asthma and to develop new methods of diagnosis, prevention and treatment. We have gained considerable experience in studies of specific antigens in inbred dogs with increased levels of serum IgE antibodies to aeroallergens. By using a new method of sensitization, combining an attenuated live virus with a specific and potent antigen, we have developed an experimental preparation that has many features resembling human asthma: High serum levels of IgE antibodies were specifically directed against ragweed antigen. Skin and airway responses to antigen were specific and reproducible. Airway responsiveness to histamine and methacholine aerosols was significantly increased in immunized dogs. Similar to human asthma, ragweed-induced bronchoconstriction in ragweed-sensitized dogs was severe and associated with profound abnormalities in cardiopulmonary function and appeared to be of greater magnitude than usually seen in Ascaris-induced reactions. Ragweed-sensitized dogs had atopic dermatitis, particularly during grass pollen season, confirmed by biopsy and described previously in atopic dogs. Ragweed-sensitized dogs did not have spontaneous wheezing, but usually had diffuse, severe wheezing during induction of anesthesia; cardiac arrhythmias were also common during anesthesia. Ragweed-sensitized dogs appeared to differ from Ascaris-sensitive dogs with respect to skin responsiveness. There was a surprisingly narrow range of skin responsiveness to antigen, whereas Snapper et al. in 1980 reported a wide range of skin responsiveness to Ascaris suum antigen in a group of mongrel dogs. Skin responsiveness to histamine was greater in ragweed-sensitized dogs than in nonimmunized dogs. Similar to human atopic patients, we found frequent late-phase reactions to ragweed antigen. As described below, we showed that antigen-induced mast cell degranulation in skin and airways was associated with inflammation which, in turn, was associated with increased airway responsiveness to pharmacologic agents. The generation of thromboxane by inflammatory cells induced by antigen challenge in ragweed-sensitized dogs appears to play a critical role in altering the response of both airways and skin to pharmacologic agonists.

Animals↗
PubMed1986

Inhibition of antigen-induced airway hyperresponsiveness by a thromboxane synthetase inhibitor (OKY-046) in allergic dogs.

To determine the role of thromboxane A2 in the airway hyperresponsiveness induced by antigen challenge, we studied the effect of a thromboxane synthetase inhibitor, OKY-046, i.e., sodium (E)-3-[4-(1-imidazolylmethyl)-phenyl]-2-propanoate, in 6 ragweed-sensitized dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus total pulmonary resistance before and 6 and 24 h after inhalation with ragweed antigen. This procedure was repeated in each dog during intravenous infusion of OKY-046 (100 micrograms/kg/min). OKY-946 did not alter the acute increase in total pulmonary resistance after antigen. At 6 h, there was a 7-fold increase in airway responsiveness, an effect that was prevented by OKY-046 (p less than 0.001). At 24 h, 18 h after OKY-046 was stopped, hyperresponsiveness was still significantly inhibited. OKY-046 did not alter the influx of neutrophils recovered by bronchoalveolar lavage performed at 6 h after antigen challenge. Antigen-induced airway hyperresponsiveness in dogs may depend upon the thromboxane A2 generation from inflammatory cells (e.g., neutrophils).

Acrylates↗
PubMed1985

An ultrastructural analysis of dog mastocytoma cells and normal mast cells.

A well-differentiated dog mastocytoma was characterized ultrastructurally using morphometric, histochemical, and biochemical methods. The ultrastructure of cells in the intact tumor was compared to the morphology of cells disaggregated from the tumor and cultured for periods as long as 4 weeks and to normal dog connective tissue mast cells. Most of the tumor cells contained histamine (mean = 5.81 pg/cell), demonstrated chloroacetate esterase activity histochemically, stained metachromatically with toluidine blue, and were similar in ultrastructure to normal dog mast cells. The proportion of mast cells in this tumor averaged 67%; eosinophils, fibroblasts, plasma cells, and macrophages also were present. The mean diameter of mast cells (12.79 micron) and the mean diameter of their cytoplasmic granules (473 nm) were similar to those reported for mast cells and mastocytoma cells from various species. The heterogeneity in appearance of the mastocytoma granules is consistent with a variable degree of granule maturation. After disaggregation or periods of culture ranging from 2 days to 4 weeks, the mean granule diameters were 15% larger than those measured in the intact mastocytoma cells, though other morphological features remained unchanged. Although the cells retained their distinct morphological features for at least 4 weeks, some of their physiological responses were lost after 1 week in culture. Our study showed that dog mastocytomas can be a source of a large, relatively homogeneous population of cells that are useful for elucidating some of the structural and functional properties of mast cells.

Animals↗
PubMed1985

Mast cell heterogeneity in dog skin.

The degree of metachromasia of mast cell granules is known to vary with the type of tissue fixation and among different tissues and species. The present study sought to determine whether mast cells in dog skin are heterogeneous with respect to fixation and staining properties. We performed skin biopsies in six anesthetized, atopic dogs and one mongrel dog. One biopsy was fixed in formalin and a second, from a parallel abdominal site, was fixed in basic lead acetate (Mota's solution). Adjacent sections from each biopsy were stained with alcian blue (1%, pH 0.5) or for chloroacetate esterase activity. In alcian blue-stained sections, one-third fewer mast cells were detected in skin fixed in formalin (1,836 +/- 454 mast cells/mm3, mean +/- SEM) than in skin fixed in basic lead acetate (2,684 +/- 527 mast cells/mm3) (P less than 0.05). The chloroacetate esterase reaction detected the larger number of mast cells regardless of the fixative used. We conclude that mast cell heterogeneity, as demonstrated by metachromatic staining following different types of tissue fixation, exists in dog skin. "Typical" mast cells stain with alcian blue regardless of fixation; however, "atypical" mast cells exhibit metachromasia only after fixation in basic lead acetate. Both the typical and atypical types of mast cells have chloroacetate esterase activity.

Alcian Blue↗
PubMed1985

Antigen-induced airway hyperresponsiveness and pulmonary inflammation in allergic dogs.

We studied whether antigen-induced airway hyperresponsiveness was associated with pulmonary inflammation in 11 anesthetized ragweed-sensitized dogs. Airway responsiveness to acetylcholine aerosol was determined before and at 2, 6, and 24 h after ragweed or sham aerosol challenge. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) performed at either 2 or 6 h. Total pulmonary resistance increased 11-fold at 5 min after ragweed. Airway responsiveness was unchanged at 2 h but was increased 6.6-fold at 6 h in 8 of 11 dogs (P less than 0.001); hyperresponsiveness persisted from 4 days to 4 mo. Airway responsiveness was unchanged by aerosols of diluent. Neutrophils in BAL fluid increased approximately sixfold at 2 h (P less than 0.02) and at 6 h (P less than 0.02) after antigen challenge. There were fewer eosinophils in fluid recovered at 6 h after antigen compared with 2 h lavages (P less than 0.05). In three nonresponders, BAL showed no significant changes in neutrophils and eosinophils after antigen. Thus antigen-induced hyperresponsiveness is associated with the presence of pulmonary inflammation, presumably arising from the airways and involving both neutrophils and eosinophils.

Acetylcholine↗
PubMed1985

Nicotine-induced respiratory effects of cigarette smoke in dogs.

We report that nicotine is responsible for both a blood-borne stimulation of the respiratory center and a direct effect on intrathoracic airway tone in dogs. We introduced cigarette smoke into the lungs of donor dogs and injected arterial blood obtained from them into the circulation of recipient dogs to show that a blood-borne material increased breathing and airway smooth muscle tone. Smoke from cigarettes containing 2.64 mg of nicotine was effective; that from cigarettes containing 0.42 mg of nicotine was not. Nicotine, in doses comparable to the amounts absorbed from smoke, also increased breathing and tracheal smooth muscle tension when injected into the vertebral circulation of recipient dogs. Finally, blockade of nicotine receptors in the central nervous system and in the airway parasympathetic ganglia inhibited the effects of inhaled cigarette smoke and intravenous nicotine on the respiratory center and on bronchomotor tone. We conclude that nicotine absorbed from cigarette smoke is the main cause of cigarette smoke-induced bronchoconstriction. It caused central respiratory stimulation, resulting in increased breathing and airway smooth muscle tension, and had a direct effect on airway parasympathetic ganglia as well.

Animals↗
PubMed1985

Airway responsiveness to inhaled antigen, histamine, and methacholine in inbred, ragweed-sensitized dogs.

We studied the responses to antigen in animals selected from a colony of inbred dogs sensitized to specific allergens to determine if they had characteristics similar to those of human asthmatics. They were immunized with ragweed and grass pollen extracts (10 micrograms in alum) immediately after routine vaccination with attenuated live virus (distemper and hepatitis) and killed bacteria (Leptospira) at 4, 8, and 12 wk of age. Subsequently, ragweed and grass injections were repeated every 2 months. Immunized dogs made specific IgE-antibodies in serum averaging 3 to 4 times that of control animals (no immunization with pollen or vaccine). They showed positive skin responses to the injection of ragweed pollen extract, whereas control dogs did not respond to ragweed pollen by quantitative skin test or inhalation challenge. In immunized dogs under barbiturate anesthesia, air-flow resistance of the total respiratory system increased from 0.60 +/- 0.07 (mean +/- SEM) before to 12.6 +/- 3.4 cm H2O/lps 5 min after the start of antigen aerosol; respiratory resistance remained increased for 20 min and was associated with 0 hypoxemia and increased arterial plasma histamine. In addition, airway responsiveness to both inhaled histamine and methacholine was greater in immunized dogs than in nonimmunized dogs of comparable age. Airway responses to each agonist were highly reproducible on repeated testing. These results indicate that physiologic responses to antigen by inbred, ragweed-sensitized dogs resemble human asthma closely and that these dogs appear suitable for a variety of experimental studies of asthma with respect to pathogenesis, diagnosis, prevention, and treatment.

Animals↗
PubMed1985

Characterization of purified dog mastocytoma cells. Autonomic membrane receptors and pharmacologic modulation of histamine release.

There is conflicting evidence as to which autonomic receptors mast cells possess and whether the receptors are capable of modulating mediator release. We have studied dog mastocytoma cells because they are available in large numbers in a relatively pure form, unlike normal dog mast cells. Mastocytoma nodules from a dog were excised and disaggregated with collagenase to provide a cell suspension of mastocytoma cells of greater than 92% purity. The presence of autonomic receptors was assessed by both radioligand binding assays and by evaluating pharmacologic modulation of mediator release. In the radioligand binding assays, beta-adrenergic receptors were estimated by [3H]dihydroalprenolol binding, alpha-adrenergic receptors by [3H]prazosin binding and cholinergic receptors by [3H]quinuclidinyl benzilate binding. Nonspecific binding was determined in each case by incubation in the presence of the specific antagonists propranolol, phentolamine, and atropine, respectively. The effect of autonomic agonists on immunologic and nonimmunologic histamine release was examined, using the beta-adrenergic agonists isoproterenol and terbutaline, the alpha-adrenergic agonist phenylephrine with and without propranolol, and the cholinergic agonist acetylcholine. Dose-response curves were constructed both for the autonomic agonists and the histamine-releasing agents. Results from the radioligand binding and the pharmacologic studies were concordant. These dog mastocytoma cells had a high density of beta-receptors (21,500 +/- 3,300; mean +/- SE beta-receptors/cell, n=5) of which the predominant subtype appeared to be beta2. No evidence was found for the presence of alpha-adrenergic or cholinergic receptors either by direct receptor binding or by their actions on histamine release.

Acetylcholine↗
PubMed1984

Immunologic release of histamine from dog lung: comparison of in vivo and in vitro responses in the same animal.

The purpose of this study was to compare, for the first time, antigen-induced histamine release from the lung in the same natively allergic dogs both in vitro and in vivo. In six dogs, maximal antigen-induced histamine release from the lung correlated closely in vitro and in vivo (r = 0.94), although it varied widely between dogs (0% to 75.5% of total tissue histamine content); similarly, the antigen concentration to produce 50% of maximal histamine release varied sixfold between dogs (40 micrograms/ml to 250 micrograms/ml). In each of five other dogs, terbutaline sulfate administered intravenously caused a dose-dependent inhibition of antigen-induced histamine release from lung fragments in vitro: the maximal inhibition produced by 1 mg/kg was 60 +/- 4.5% (mean +/- SEM). In these same dogs, 10(-5)M terbutaline incubated with lung fragments in vitro caused inhibition of antigen-induced histamine release comparable to 1 mg/kg terbutaline in vivo. Increasing the dose of terbutaline in vitro produced maximal inhibition at 10(-4)M with no greater effect of the drug at 10(-3)M (71.4 +/- 3.8% inhibition). In both experimental situations propranolol caused a dose-dependent inhibition of beta-adrenergic modulation of Ascaris-induced release of histamine. This result supports the conclusion that terbutaline produced its effects by actions mediated by beta-adrenergic receptors on pulmonary mast cells. This experimental approach provides a suitable preparation in which to estimate the effective dose of agonists that modulate antigen-induced mast cell function in vivo.

Animals↗
PubMed1984

Radioenzymatic assay for measurement of tissue concentrations of histamine: adaptation to correct for adherence of histamine to mechanical homogenizers.

Because adherence of histamine to glass is well-known, we tested for its adherence to a mechanical homogenizer commonly used in the extraction of histamine from tissue samples. During 60 sec of homogenization, 15% to 17% of the histamine originally present in the samples "disappeared," and the reason for the disappearance was reversible binding of histamine to the homogenizer. Adding trace amounts of [14C]histamine to each sample before homogenization and measuring the disappearance of radioactivity during homogenization permitted correction for binding to the homogenizer. This technique for correction was validated by the measurement of endogenous concentrations of histamine in the tracheal posterior membranes of six dogs (range of mean concentrations: 0.63 to 1.51 ng/mg wet weight) followed by the measurement of known amounts of exogenous histamine added before homogenization to tracheal tissue samples from the same dogs. In the latter samples, 96 +/- 13% (mean +/- SEM) of the histamine added was measured by our technique. We conclude that binding of histamine to mechanical homogenizers may be an important cause of inaccuracy of the enzymatic assay for the measurement of histamine concentrations in tissue but that such binding may but that such binding may be easily corrected for.

Adhesiveness↗
PubMed1984

Localization of cAMP in dog and cat trachea: effects of beta-adrenergic agonists.

Adenosine 3',5'-cyclic monophosphate (cAMP) is believed to mediate the transport of ions, water, and mucous glycoproteins in the respiratory tract. Because chemical measurements of total tissue levels of cAMP may not always reflect changes in specific cell types, we adapted standard immunocytochemical methods to examine the cellular localization of cAMP in dog and cat tracheae. The beta-adrenergic agonists terbutaline and isoproterenol increased immunoreactive cAMP in ciliated epithelial cells of dog and cat tracheae and in both serous and mucous gland cells of cat tracheae. Epithelial goblet cells did not respond to beta-adrenergic agonists in either species. This study provides information about the location of beta-receptors on individual cells in the trachea that is not available from chemical assays of either cAMP or beta-receptors in these tissues. Our results support the hypothesis that secretory functions in both serous and mucous submucosal gland cells and ciliated epithelial cells, but not goblet cells, may involve cyclic AMP-dependent mechanisms.

Animals↗
PubMed1984

Cigarette smoke-induced bronchoconstriction in dogs: vagal and extravagal mechanisms.

We reassessed the severity of cigarette smoke-induced bronchoconstriction and the mechanisms involved in anesthetized dogs. To evaluate the severity of smoke-induced bronchoconstriction, we measured airway pressure and airflow resistance (Rrs, forced oscillation method). We studied the mechanisms in other dogs by measuring airway pressure, central airway smooth muscle tone in tracheal segments in situ, and respiratory center drive by monitoring phrenic motor nerve output, including the role of vagal and extravagal nerves vs. the role of blood-borne materials during inhalation of cigarette smoke. Rrs increased more than fourfold with smoke from one cigarette delivered in two tidal volumes. About half the airway response was due to local effects of smoke in the lungs. The remainder was due to stimulation of the respiratory center, which activated vagal motor efferents to the airway smooth muscle. Of this central stimulation, about half was due to blood-borne materials and the rest to vagal pulmonary afferents from the lungs. We conclude that inhalation of cigarette smoke in dogs causes severe bronchoconstriction which is mediated mainly by extravagal mechanisms.

Airway Resistance↗
PubMed1984

Correlation between serial pulmonary function tests and fiberoptic bronchoscopy in patients with Pneumocystis carinii pneumonia and the acquired immune deficiency syndrome.

The records of 9 adult male patients with the acquired immune deficiency syndrome (AIDS) and biopsy-proved Pneumocystis carinii pneumonia were reviewed to determine the correlation between serial pulmonary function tests and the presence or absence of Pneumocystis organisms in subsequent bronchoscopy specimens. At diagnosis, total lung capacity (TLC) or vital capacity (VC) was abnormally low in 4 patients (44%) and diffusing capacity (DLCO) was abnormally low in 8 patients (89%). The ratio of forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) was elevated in all patients. After 21 to 47 days of specific therapy for Pneumocystis pneumonia, changes in DLCO, TLC, VC, and FEV1/FVC did not correlate with the presence or absence of Pneumocystis organisms in bronchoscopy specimens from 7 patients. However, changes in DLCO 105 to 258 days after diagnosis seemed to correlate with the late response to treatment in 6 patients. These results suggest that decisions to terminate specific therapy for Pneumocystis pneumonia in patients with AIDS should not be based on short-term changes in pulmonary function.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Prostaglandins and intracellular cyclic AMP in respiratory secretory cells.

Prostaglandins are known to affect ion transport and mucus secretion in the trachea, and at least part of their effect is thought to be mediated by cyclic AMP. Because no prostaglandin receptor assay is currently available, we have used an immunocytochemical probe for the intracellular localization of cyclic AMP to identify those specific cell types in dog and cat trachea that respond to prostaglandins. Using tracheal explants similar to those used by other investigators for in vitro studies of ion transport and glycoprotein secretion, we examined the effect of endogenous and exogenous prostaglandins on immunoreactive cyclic AMP. Endogenous prostaglandins, which may be secreted in response to minor distortion of tissue membranes, stimulated immunoreactive cyclic AMP in ciliated epithelial cells and in both serous and mucous submucosal gland cells. This was not observed in tissues assayed 60 min after dissection, or dissected in the presence of indomethacin or of BW755C. Exogenous prostaglandin E1 increased cyclic AMP in these same cell types. We conclude that prostaglandins stimulate cyclic AMP in specific cell types in the trachea, and that endogenous prostaglandins play a major role in many in vitro preparations.

Animals↗
PubMed1983

Stimulus specificity of the generation of leukotrienes by dog mastocytoma cells.

Isolated dog mastocytoma cells sensitized with dog anti-ragweed IgE and challenged with ragweed antigen or incubated with ionophore A23187 or the carboxy-terminal dodecapeptide of platelet factor 4, PF4(59-70), release histamine and concurrently generate leukotrienes B4, C4, and D4. In contrast, the exposure of mastocytoma cells to 0.1-3 micrograms/ml of 15-hydroxyeicosatetraenoic acid (15-HETE) stimulates selectively the generation of leukotrienes, in the absence of histamine release, while 0.1-1 micrograms/ml of compound 48/80 releases histamine without enhancing the generation of leukotrienes. That natural stimuli are capable of selectively activating one synthetic or secretory compartment of mast cells suggests that separate subsets of receptors as well as different biochemical events may serve to mobilize each class of mediators.

Allergens↗
PubMed1983

Effect of beta-adrenergic stimulation on experimental canine anaphylaxis in vivo.

We studied beta-adrenergic modulation of antigen-induced release of histamine and changes in lung function in natively allergic, anesthetized dogs. After thoracotomy and bilateral cervical vagotomy, samples of peripheral lung frozen in situ were obtained for measurement of adenosine cyclic 3',5'-monophosphate (cAMP) and histamine. In 11 dogs with beta-adrenergic blockade (propranolol), subsequent Ascaris suum antigen (intravenous) decreased lung tissue histamine 21.5% +/- 5.3% (mean +/- SE), with marked physiologic changes of anaphylaxis. In six other dogs, with no pharmacologic treatment before antigen, A. suum decreased lung tissue histamine only 11.5% +/- 1.9%. In six other dogs, terbutaline (1 mg/kg, i.v.) increased concentration of cAMP in peripheral lung, indicating stimulation of beta-adrenergic receptors, and inhibited response to A. suum. When a beta-adrenergic agonist was given 15 sec prior to A. suum, cAMP doubled and inhibition was incomplete. When a beta-agonist was given 150 sec prior to A. suum, cAMP increased fivefold and inhibition was complete.

Adrenergic beta-Agonists↗
PubMed1983

Biochemical and physiological effects of compound 48/80 on canine trachea in vivo.

We studied changes in tracheal histamine content and tracheal muscle tension after degranulation of tracheal mast cells by compound 48/80 in 32 anesthetized dogs. In four dogs compound 48/80 caused an increase in tracheal tension [13 +/- 5 (SD) g/cm], while femoral arterial blood pressure decreased only 14 +/- 11%. Tracheal tissue histamine decreased 17 +/- 6% in five dogs receiving intra-arterial compound 48/80 (5 X 10(-3) to 10(-1) mg/kg). Chlorpheniramine, an H1-antagonist, selectively inhibited tracheal contraction to compound 48/80 and histamine. Cimetidine, an H2-antagonist, did not alter the response to intra-arterial histamine. In 11 dogs, the doses of both intra-arterial histamine and acetylcholine required to produce a threshold increase in tracheal tension of 8 g/cm were compared. Threshold doses for acetylcholine varied 10-fold, compared with 100-fold variation for histamine among these dogs. There was a significant correlation between increased tracheal tension produced by compound 48/80 and histamine (r = 0.62). We conclude that compound 48/80 causes a variable increase in tracheal tension in vivo because of marked variability in the H1-receptor response of tracheal smooth muscle to histamine and because of variability in the release of mediator from respiratory mast cells by compound 48/80.

Acetylcholine↗