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Biomedical subjects

M J Holtzman

Publications and source records attributed to M J Holtzman.

At least 73 records · Page 4Linked to original sources
PubMed1984

Neutrophil depletion inhibits airway hyperresponsiveness induced by ozone exposure.

We studied whether ozone-induced hyperresponsiveness could be inhibited by neutrophil depletion in dogs. Responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance; depletion was assessed by counting neutrophils in venous blood and in biopsies of the airway epithelium. Responsiveness and neutrophil numbers were determined 5 days and 1 day before ozone and 1 h after ozone (3.0 ppm, 2 h) in 6 untreated dogs and in 6 dogs treated with hydroxyurea (200 mg/kg daily for 5 days starting 5 days before ozone). In untreated dogs, responsiveness and neutrophil numbers 5 days and 1 day before ozone did not change, but responsiveness and epithelial neutrophils increased markedly after ozone. In treated dogs, circulating neutrophils decreased from 8.9 +/- 2.2 to 0.6 +/- 0.01 X 10(3) per mm3 (mean +/- SEM), and responsiveness before ozone did not change. Furthermore, increases in responsiveness and epithelial neutrophils did not occur after ozone. Six wk after stopping hydroxyurea, responsiveness and epithelial neutrophils increased markedly after ozone. The results suggest that ozone-induced hyperresponsiveness may depend on the mobilization of neutrophils into the airways.

Animals↗
PubMed1984

Indomethacin inhibits the airway hyperresponsiveness but not the neutrophil influx induced by ozone in dogs.

To determine whether oxygenation products of arachidonic acid may be involved in the airway hyperresponsiveness induced by ozone exposure, we studied whether ozone-induced hyperresponsiveness could be inhibited by the prostaglandin synthetase inhibitor, indomethacin, in dogs. Airway responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance in 2 sets of experiments: in one set, 5 dogs were given no indomethacin treatment and were studied both before and after ozone exposure (3.0 ppm, 2 h); in another set, the same dogs were studied before indomethacin treatment or ozone exposure and then during treatment (1 mg/kg every 12 h for 4 days) both before and after ozone exposure. On each occasion, we also determined the number of neutrophils in biopsies of the airway epithelium. When the dogs were not treated with indomethacin, ozone caused a marked increase in responsiveness to acetylcholine and a marked increase in the number of neutrophils in the airway epithelium. When the dogs were given indomethacin, responsiveness was no different during treatment than before treatment, but more importantly, responsiveness did not increase significantly after they were exposed to ozone. Interestingly, indomethacin treatment did not affect either the baseline number of epithelial neutrophils before ozone exposure or the increase in the number of neutrophils after exposure. The results suggest that oxygenation products of arachidonic acid that are sensitive to inhibition by indomethacin play a role in ozone-induced hyperresponsiveness without affecting the influx of neutrophils.

Animals↗
PubMed1984

Airway hyperresponsiveness and changes in cell counts in bronchoalveolar lavage after ozone exposure in dogs.

We studied whether airway hyperresponsiveness induced by ozone exposure is associated with changes in the numbers of different types of cells in bronchoalveolar lavage in dogs. Airway responsiveness to acetylcholine and the numbers of cells in lavage fluid were determined 1 wk before and then 1 h and 1 wk after 2-h exposures to filtered air and to ozone (3.0 ppm) in each of 5 dogs. Airway responsiveness and the numbers of cells in lavage fluid did not change after exposure to filtered air. By contrast, airway responsiveness increased markedly 1 h after exposure to ozone and returned to control levels 1 wk later. In addition, the numbers of neutrophils and of ciliated epithelial cells in lavage increased markedly 1 h after ozone and returned to control levels 1 wk later. Our previous study showed that airway hyperresponsiveness induced by ozone is associated with an influx of neutrophils into the most central airways (1); the present results suggest that the hyperresponsiveness is also accompanied by an influx of neutrophils into more distal airways and by desquamation of airway epithelial cells.

Airway Resistance↗
PubMed1983

Selective generation of leukotriene B4 by tracheal epithelial cells from dogs.

The incubation of suspensions of canine tracheal epithelial cells of greater than 95% purity with arachidonic acid (25-200 micrograms/ml) for 60-120 min resulted in the generation of a maximum of 36.2 +/- 9.1 picomoles of leukotriene B4/10(6) cells, less than 2.0 picomoles of leukotrienes C4, D4, and E4/10(6) cells, and 1030 +/- 463, 767 +/- 500, and 324 +/- 100 picomoles/10(6) cells of 15-, 12-, and 5-hydroxy-eicosatetraenoic acids, respectively (mean +/- SEM, n = 8). The identity of leukotriene B4 was established by chromatographic and spectral properties, by reactivity with mono-specific anti-plasma, and by the chemotactic activity for neutrophils. Thus, the epithelium may be an important source of mediators of inflammation and hypersensitivity of pulmonary airways.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1983

Effect of route of atropine delivery on bronchospasm from cold air and methacholine.

We undertook a study to determine whether the apparent disparity between the dose of inhaled atropine required to inhibit the bronchoconstriction induced by inhaled methacholine and the dose required to inhibit the bronchoconstriction induced by eucapnic hyperpnea with cold air is a function of the route of administration of atropine. In six subjects with asthma, we constructed dose-response curves to inhaled methacholine and to eucapnic hyperpnea with cold air after treatment with inhaled atropine (0.5 mg delivered) and intravenous placebo, with inhaled placebo and intravenous atropine (0.5 mg injected), and with inhaled and intravenous placebos. Atropine by either route shifted the dose-response curves to both cold air and to methacholine to the right. In every subject, however, inhaled atropine caused a markedly greater rightward shift of the inhaled methacholine dose-response curve than did intravenous atropine, whereas inhaled and intravenous atropine had similar effects on the cold air dose-response curve. These findings suggest that the apparent disparity between the doses of atropine required to inhibit methacholine- and cold air-induced bronchoconstriction may be a function of the route of administration of atropine and thus does not imply a nonmuscarinic action of atropine. The findings support the view that cold air causes bronchoconstriction via muscarinic pathways.

Adult↗
PubMed1983

Intravenous versus inhaled atropine for inhibiting bronchoconstrictor responses in dogs.

We studied whether the muscarinic antagonist, atropine, given intravenously or by inhalation, inhibits the bronchoconstrictor responses to inhaled acetylcholine and to acetylcholine released by electrical stimulation of the vagus nerves to the same degree. We assessed bronchoconstrictor responses in anesthetized dogs by determining the increase in total pulmonary resistance before and after increasing doses of atropine and then constructing inhibition dose-response curves. Before atropine the responses to the two stimuli were equal in magnitude. After intravenous atropine (initial dose 0.12 micrograms/kg, total dose 16 micrograms/kg) both responses were progressively inhibited to a similar degree. By contrast, after inhaled atropine (initial dose 0.02 micrograms/kg, total dose 2.4 micrograms/kg) the response to acetylcholine inhalation was inhibited to a much greater degree than the response to vagal stimulation. Thus, in studies designed to inhibit bronchoconstriction due to an inhaled muscarinic agonist to the same degree as bronchoconstriction due to a vagal reflex, atropine might better be given intravenously than by inhalation.

Aerosols↗
PubMed1983

Time course of airway hyperresponsiveness induced by ozone in dogs.

To better understand the mechanism of ozone-induced airway hyperresponsiveness we determined the time course of the ozone effect in dogs. To do this we assessed airway responsiveness before ozone exposure and then at 1 h, 1 day, and 1 wk after ozone exposure. To assess responsiveness we anesthetized the dogs and obtained dose-response curves of increasing concentrations of acetylcholine or histamine aerosols delivered to the airways vs. pulmonary resistance. Ozone exposures were carried out with the dogs awake and at rest in an exposure chamber for 2 h breathing either through the nose and mouth at a level of 2.2 ppm or through a tracheostomy at a level of 1.0 ppm. For both acetylcholine and histamine and for both routes of ozone delivery airway responsiveness increased most markedly at 1 h after ozone, increased to a lesser degree 1 day later, and returned to control levels by 1 wk. The results are similar to our previous studies in humans that showed that ozone-induced hyperresponsiveness occurs shortly after exposure and is rapidly reversible and suggest that the ozone effect is linked to an acute inflammatory response in the airways.

Acetylcholine↗
PubMed1983

Importance of airway inflammation for hyperresponsiveness induced by ozone.

We studied whether ozone-induced airway hyperresponsiveness correlates with the development of airway inflammation in dogs. To assess airway responsiveness, we determined increases in pulmonary resistance produced by delivering acetylcholine aerosol to the airways. To assess airway inflammation, we biopsied the airway mucosa and counted the number of neutrophils present in the epithelium. Airway responsiveness and inflammation were assessed in anesthetized dogs before ozone exposure and then 1 h and 1 wk after ozone (2.1 ppm, 2 h). Airway responsiveness increased markedly at 1 h after ozone and returned to control levels 1 wk later in each of 6 dogs, but it did not change after ozone in another 4 dogs. Furthermore, dogs that became hyperresponsive also developed a marked and reversible increase in the number of neutrophils in the epithelium, whereas dogs that did not become hyperresponsive had no change in the number of neutrophils. For the group of dogs, the level of airway responsiveness before and after ozone exposure correlated closely with the number of epithelial neutrophils. The results suggest that ozone-induced airway hyperresponsiveness may depend on the development of an acute inflammatory response in the airways.

Acetylcholine↗
PubMed1983

Antihistaminic versus anticholinergic effects of atropine on canine trachealis muscle.

To determine antihistaminic versus anticholinergic effects of atropine in airway smooth muscle, we used an in vitro preparation of canine trachealis muscle strips and determined atropine's effect on contractile responses induced by histamine or by electrical field stimulation of cholinergic nerves. In the first series of experiments, 53 strips had initial responses to field stimulation determined and were then randomly assigned to a control group or to a group treated with atropine before field stimulation was repeated and histamine was given. Atropine in concentrations of 10(-8), 10(-7), and 10(-6) M decreased the response to field stimulation to 61.4, 10.5, and 0% of the initial response, respectively, but had no effect on the responses to histamine. In the second series of experiments, 24 strips were treated with indomethacin to prevent histamine tachyphylaxis; these strips had initial responses to both field stimulation and histamine determined and were then assigned to a control group or to a group treated with atropine before field stimulation and histamine were repeated. In these experiments, a concentration of atropine (10(-6) M), which again completely blocked the response to field stimulation, still had no effect on histamine-induced contraction. We conclude that atropine in a concentration that completely blocks the response to cholinergic nerve stimulation has no antihistaminic effect.

Animals↗
PubMed1982

Interaction of serotonin with vagal- and ACh-induced bronchoconstriction in canine lungs.

The bronchoconstrictor response to electrical stimulation of the peripheral ends of both cut cervical vagus nerves was potentiated by serotonin aerosols in 10 experiments in 7 anesthetized dogs. The bronchoconstrictor response to acetylcholine (ACh) aerosols was unchanged after serotonin. We conclude that serotonin acts at the level of the parasympathetic ganglia or the postganglionic nerve terminal to potentiate the bronchoconstrictor response to vagal stimulation.

Acetylcholine↗
PubMed1982

Selective effect of general anesthetics on reflex bronchoconstrictor responses in dogs.

To determine which part of the parasympathetic bronchoconstrictor pathway is most sensitive to depression by general anesthetics, we stimulated different parts of the pathway in dogs after initial anesthesia with chloralose and urethan and then after additional anesthetic drugs. We stimulated the entire reflex pathway by producing apnea or hypoventilation, the sensory pathway by electrically stimulating the proximal end of cut superior laryngeal nerves, and the motor pathway by stimulating the distal end of a cut cervical vagus nerve. Bronchoconstrictor responses to all stimuli were assessed with a bypassed tracheal segment. When no additional anesthetic was administered, responses to all stimuli increased with time. Small additional doses of anesthetics (thiopental, 1-5 mg/kg; pentobarbital, 1-2 mg/kg; amobarbital, 1-2 mg/kg; or chloralose, 10 mg/kg) decreased responses to reflex and sensory stimulation markedly and reversibly, but they did not affect responses to motor stimulation. Increased doses decreased responses to motor stimulation as well. Our previous study (Skoogh et al., Am. Rev. Respir. Dis. 123: 202, 1981) showed that barbiturates depress parasympathetic ganglionic synapses; the present study suggests that central nervous system synapses may be even more sensitive to depression by general anesthetics.

Amobarbital↗
PubMed1982

Dose-dependent inhibition of cold air-induced bronchoconstriction by atropine.

We undertook a study to demonstrate whether inhalation of atropine could inhibit cold air-induced bronchoconstriction in a dose-dependent fashion. In seven subjects with asthma we assessed the effects of placebo and of various doses of inhaled atropine (0.13-2.08 mg) on a base-line specific airway resistance (sRaw) and on the increase in sRaw produced by 5 min of voluntary eucapnic hyperventilation with subfreezing air at -17 degrees C. We also assessed the effect of the lowest doses of atropine on the increase in sRaw produced by five breaths of 1.0% metacholine. Atropine in doses of 0.13 or 0.26 mg caused a maximal reduction in base-line sRaw and completely inhibited the effect of 1.0% methacholine on sRaw, but it did not inhibit the bronchomotor response to cold air. Higher doses of atropine did inhibit the effect of cold air on sRaw in a dose-dependent fashion. The dose of atropine required to inhibit this effect of cold air varied with the increase in sRaw produced by cold air after placebo. These results suggest that cold air causes bronchoconstriction through vagal pathways and that higher doses of antimuscarinic agents are required to inhibit vagally mediated bronchoconstriction than those required to reduce base-line airway tone or to inhibit the effects of a large dose of an inhaled muscarinic agonist.

Adult↗
PubMed1982

Barbiturates depress vagal motor pathway to ferret trachea at ganglia.

To determine which site in the vagal motor pathway to airway smooth muscle is most sensitive to depression by barbiturates, we recorded isometric muscle tension in vitro and stimulated the vagal motor pathway at four different sites before and after exposure to barbiturates. In isolated tracheal rings from ferrets, we stimulated muscarinic receptors in the neuromuscular junction by exogenous acetylcholine, postganglionic nerve fibers by electrical fluid stimulation, and the postsynaptic membrane in ganglia by 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). We also developed a tracheal nerve-muscle preparation to stimulate preganglionic fibers in the vagus nerve electrically. Activation of ganglia by DMPP or by vagus nerve stimulation was depressed by barbiturates at 10-fold lower concentrations than those depressing the activation of postganglionic nerves or the neuromuscular junction. These findings suggest that the postsynaptic membrane in parasympathetic ganglia is the site in the vagal motor pathway most sensitive to depression by barbiturates.

Animals↗
PubMed1981

Threshold concentration of ozone causing an increase in bronchial reactivity in humans and adaptation with repeated exposures.

To determine the lowest concentration of ozone that causes an increase in bronchial reactivity to histamine and to determine whether adaptation to this effect of ozone develops with repeated exposures, we studied 19 healthy adult subjects. Bronchial reactivity was assessed by measuring the rise in specific airway resistance (delta SRaw) produced by inhalation of 10 breaths of histamine aerosol (1.6% solution). In 5 subjects, bronchial reactivity was determined at 9:00 and 11:30 A.M. on 4 consecutive days without exposure to ozone (Group I). In 7 other subjects (Group II), bronchial reactivity was assessed at 9:00 and 11:30 A.M. on 3 consecutive days, and subjects were exposed to 0.2 ppm of ozone from 9:30 to 11:30 A.M. on the third day. Seven additional subjects (Group III) had bronchial reactivity assessed in a similar fashion for 2 days and then again on 3 consecutive days of 2-h exposures to 0.4 ppm of ozone. Pre-exposure bronchial reactivity of the groups was the same, and no change in bronchial reactivity occurred in the group tested repeatedly but not exposed to ozone. An increase in delta SRaw provoked by histamine was noted after the first exposure to 0.4 ppm but not to 0.2 ppm of ozone (p less than 0.025). With 3 repeated 2-h exposures to 0.4 ppm on consecutive days, however, the delta SRaw produced by histamine progressively decreased, returning to pre-exposure values after the third exposure. Our results indicate that the threshold concentration of ozone causing an increase in bronchial reactivity in healthy human subjects is between 0.2 and 0.4 ppm, and that adaptation to this effect of ozone develops with repeated exposures. The threshold concentration of ozone identified in other studies as causing changes in symptoms, lung volumes, or airway resistance was also between 0.2 and 0.4 ppm, and the time course of the development of tolerance to ozone in these other studies was similar to hat observed in our study. We propose that the appearance of symptoms, changes in pulmonary function, and the increase in bronchial reactivity may be caused by a change in the activity of afferent nerve endings in the airway epithelium.

Adaptation, Physiological↗
PubMed1980

Effect of ganglionic blockade on bronchial reactivity in atopic subjects.

To determine the site in the parasympathetic pathway responsible for the increased bronchial reactivity in 5 atopic subjects, we studied the effect of premedication with aerosols of hexamethonium, a ganglionic blocking agent, and atropine, a postganglionic blocking agent, on the bronchomotor responses to histamine and methacholine aerosols. After 7 mg of aerosolized atropine, baseline specific airway resistance (SRaw) decreased, and the increases in SRaw produced by histamine and by methacholine were prevented in each subject (p < 0.001). After 1 g of hexamethonium, baseline SRaw was decreased to a similar level, and the increase in SRaw produced by histamine was again Prevented in each subject (P < 0.001); However, the increase in SRaw produced by methacholine was not affected significantly in 3 subjects (p > 0.5) and was increased or decreased only slightly in 2 subjects (p < 0.05). These results suggest that bronchial hyperreactivity in atopic subjects may be due to a change in the characteristics of the efferent parasympathetic pathway at a site distal to the ganglion, possibly at the smooth muscle, and that bronchodilation caused by atropine and hexamethonium cannot, by itself, account for their effects on bronchomotor responses.

Adult↗