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Biomedical subjects

D Sheppard

Publications and source records attributed to D Sheppard.

At least 127 records · Page 7Linked to original sources
PubMed1987

The roles of pH and ionic species in sulfur dioxide- and sulfite-induced bronchoconstriction.

Sulfur dioxide (SO2) and sulfites are well-described causes of bronchoconstriction in persons with asthma that are chemically related and, therefore, may share a common mechanism of action. When either sulfur species dissolves in aqueous solutions, a pH-dependent equilibrium is established predominantly among bisulfite ion (HSO3-), sulfite ion (SO3=), and SO2. In addition, hydrogen ions may be released. To assess the relative bronchoconstricting potencies of these chemical forms and the role of acidity caused by the release of hydrogen ions in SO2- and sulfite-induced bronchoconstriction, we administered to 10 asthmatic subjects nebulized sodium sulfite (Na2SO3) solutions at pH 9 containing 95% sulfite, at pH 6.6 containing 80% bisulfite, and at pH 4 containing 99% bisulfite but greater than an order of magnitude more SO2 than the pH 6.6 solutions. Subjects inhaled increasing concentrations of aerosolized Na2SO3 at each pH during 1 min of tidal breathing. Subjects also breathed buffered acetic acid aerosols with the same acidity of the pH 4 Na2SO3 solutions to control for the airway effects of acid aerosols. To assess sensitivity to SO2 gas, subjects inhaled increasing concentrations of SO2 during eucapneic hyperpnea. Bronchoconstrictor response was assessed by measuring specific airway resistance (SRaw) before and after each challenge. Nine of the 10 subjects developed bronchoconstriction after inhaling the Na2SO3 aerosols at all 3 levels of pH and the SO2 gas. The mean concentration of Na2SO3 solution calculated to increase SRaw by 100% above baseline was significantly different (p less than 0.01) at the various levels of pH: pH 4 (0.17 mg/ml) less than pH 6.6 (0.49 mg/ml) less than pH 9 (2.10 mg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1987

The role of titratable acidity in acid aerosol-induced bronchoconstriction.

We evaluated the importance of pH, titratable acidity, and specific chemical composition in acid aerosol-induced bronchoconstriction in 8 asthmatic subjects. We administered aerosols of HCl and H2SO4 at pH 2.0 in an unbuffered state and buffered with glycine. The buffered acids were given in order of increasing titratable acidity (defined as the number of ml of 1 N NaOH required to neutralize 100 ml of acid solution to pH 7.0). Each set of buffered or unbuffered acid aerosols was given on a separate day and each aerosol was inhaled through a mouthpiece during 3 min of tidal breathing. Bronchoconstriction was assessed by measurement of specific airway resistance (SRaw) before and after inhalation of each aerosol. SRaw increased by more than 50% above baseline in 1 of 8 subjects after inhalation of unbuffered HCl and in no subjects after inhalation of unbuffered H2SO4, even at pH 2.0. In contrast, SRaw increased by greater than 50% in all 8 subjects after inhalation of HCl and glycine at pH 2.0 and 7 of 8 subjects after inhalation of H2SO4 and glycine at pH 2.0. The mean titratable acidity required to increase SRaw by 50% above baseline was calculated for each challenge by linear interpolation; these values for H2SO4 and glycine (5.1 ml of 1 N NaOH) and HCl and glycine (2.2 ml of 1 N NaOH) were slightly, but significantly, different (p = 0.01) and were considerably higher than the titratable acidity of the unbuffered acids at pH 2 (1.0 ml of 1 N NaOH).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Apparent effect of catalase on airway edema in guinea pigs. Role of endotoxin contamination.

The airway edema that develops in guinea pigs after exposure to toluene diisocyanate (TDI) requires the presence of polymorphonuclear leukocytes (PMN). To determine whether this airway edema is mediated by the release of hydrogen peroxide from PMN, we treated animals intravenously with catalase bound to polyethylene glycol and examined the extravasation of Evans blue dye into the tracheal wall after exposure to air or 3 ppm TDI for 1 h. Catalase (25,000, 100,000, and 300,000 IU/kg) caused a dose-dependent inhibition of the TDI-induced increase in dye extravasation. However, treatment with catalase, inactivated at the peroxide binding site with 3-aminotriazole, inhibited dye extravasation after exposure to TDI as effectively as the equimolar 100,000 IU/kg dose of active catalase. Injection of polyethylene glycol alone was without effect. Dose-dependent decreases in extravascular migration of PMN and in circulating PMN also were noted after catalase treatment. These results suggest that the catalase preparations used in these studies inhibited the PMN-dependent airway edema by an effect other than hydrogen peroxide scavenging. Examination of this and other commercially available catalase preparations revealed trace concentrations of endotoxin at levels that could be responsible for the observed effects on PMN function. Treatment of animals with doses of Escherichia coli endotoxin similar to those inadvertantly administered to the catalase-treated groups (0.1 ng/kg to 100 ng/kg, intravenously) inhibited TDI-induced extravasation of Evans blue dye in a dose-dependent manner. These results suggest that contaminating endotoxin may contribute to some of the protective effects of preparations of catalase observed in previous studies of vascular permeability.

Animals↗
PubMed1987

Physiology of the parasympathetic nervous system of the lung.

Parasympathetic nerves play an important role in modulating smooth muscle tone and mucus secretion in the airways. This modulation can occur through a variety of afferent inputs, from the central nervous system, at parasympathetic ganglia, and on post-ganglionic efferent fibres themselves. Abnormalities at any of these sites could, and in some patients probably do, contribute to the abnormalities in smooth muscle contraction and mucus secretion that characterize a number of airway diseases, including asthma. Because these pathways play little or no role in the exaggerated bronchoconstrictor responses in many patients, however, an abnormality of the parasympathetic pathway cannot be the sole explanation for abnormal airway hyperresponsiveness.

Bronchi↗
PubMed1986

Acute effects of routine firefighting on lung function.

We undertook a study to determine the acute effects of routine firefighting on lung function and the relationship between these acute effects and nonspecific airway responsiveness. For 29 firefighters from a single fire station, we calculated the concentration of methacholine aerosol that caused a 100% increase in specific airway resistance (Pc100). Over an 8-week period we than measured FEV1 and FVC in each firefighter before and after each 24-hr workshift and after every fire. From 199 individual workshifts without fires, we calculated the mean +/- 2 SD across-workshift change in FEV1 and FVC for each firefighter. Eighteen of 76 measurements obtained within 2 hr after a fire (24%) showed a greater than 2 SD fall in FEV1 and/or FVC compared to two of 199 obtained after routine workshifts without fires (1%; p less than .001). On 13 of 18 occasions when spirometry decreased significantly, we obtained repeat spirometry (postshift) 3-18.5 hr after fires, and on four of these occasions FEV1 and/or FVC were still more than 2 SD below baseline. Decrements in spirometry occurred as often in firefighters with high Pc100s as in those with low Pc100s. In two firefighters in whom FEV1 and FVC fell by more than 10% after fires, we repeated measurements of methacholine sensitivity, and it was increased over the prestudy baseline. These findings suggest that routine firefighting is associated with a high incidence of acute decrements in lung function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Effects of esmolol on airway function in patients with asthma.

In a double-blind, randomized, crossover study in ten patients with asthma, the effects on specific airway resistance of esmolol, a new ultra-short-acting beta 1-selective adrenoceptor blocker, were compared with those of placebo. Specific airway resistance was measured during increasing doses of esmolol infusion, during dry air provocation tests, and following isoproterenol inhalation. These same studies were later carried out on six of ten patients following intravenous propranolol infusion. All patients were able to tolerate the maximum dose of esmolol (300 micrograms/kg/min); treatment differences between esmolol and placebo were not found. In contrast, intravenous propranolol produced marked symptomatic bronchoconstriction after the lowest dose (1 mg) in two of six patients. Esmolol produced slight but statistically significant enhancement of patients' sensitivity to dry air provocation. Similarly, a slight but significant inhibition of bronchomotor sensitivity to isoproterenol was noted during esmolol infusion. After infusion of 5 mg of intravenous propranolol, one of four patients had a clinically significant increase in sensitivity to dry air. It is concluded that esmolol, because of its short duration of action and relative lack of effect on airway resistance, may be preferred over propranolol in patients with asthma who require treatment with an intravenous beta-blocking agent.

Adrenergic beta-Antagonists↗
PubMed1986

Granulocyte-mediated airway edema in guinea pigs.

To determine the role of polymorphonuclear leukocytes (PMNs) in the airway edema that accompanies airway inflammation, we studied the effects of a 1-h exposure to 2 ppm toluene diisocyanate (TDI) on tracheal extravasation of Evans blue dye and on the concentration of PMNs in the tracheal wall. Tracheal Evans blue content was significantly increased by TDI exposure (53.6 +/- 8.0 micrograms/g tracheal tissue (mean +/- SE) for animals exposed to TDI and 16.3 +/- 2.0 for animals exposed to air, P less than 0.0025) as were both the intravascular and extravascular concentration of PMNs in tracheal sections (intravascular PMNs were 28.0 +/- 8.4 X 10(3) cells/mm3 for TDI and 1.5 +/- 1.5 X 10(3) for air, P less than 0.025, extravascular PMNs were 10.9 +/- 4.5 X 10(3) for TDI and 0 for air, P less than 0.05). PMN depletion with vinblastine or with hydroxyurea abolished both the increase in tracheal Evans blue extravasation and the increase in the concentration of intravascular and extravascular PMNs in animals exposed to TDI. PMN depletion with hydroxyurea did not significantly inhibit the increase in tracheal Evans blue extravasation caused by intravenous histamine. Administration of donor PMNs to animals depleted of PMNs with hydroxyurea reconstituted the TDI-induced increase in tracheal Evans blue extravasation (80.4 +/- 17.3 micrograms/g tissue (mean +/- SE) in animals exposed to TDI vs. 21.3 +/- 2.9 in animals exposed to air, P less than 0.025) and in the intravascular concentration of PMNs in tracheal sections [18.5 +/- 3.4 X 10(3) cells/mm3 (mean +/- SE) in animals exposed to TDI vs. 1.3 +/- 1.3 X 10(3) in animals exposed to air, P less than 0.0025].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

The usefulness of induced sputum in the diagnosis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome.

Thirty-two patients with or suspected of having the acquired immunodeficiency syndrome were evaluated for opportunistic lung infection using examination of sputum induced by inhalation of 3% saline. The specimens obtained were stained with Giemsa stain and examined for Pneumocystis carinii. Smears of sputum were also appropriately stained and examined for acid-fast organisms and fungi, as well as cultured for these organisms. Patients whose sputum did not contain P. carinii had bronchoscopy within 24 h of sputum induction. Twenty-five of the 32 patients were ultimately determined to have P. carinii pneumonia. Of these, 14 were detected by examination of sputum (sensitivity, 56%). Of 18 patients whose sputum did not contain P. carinii, 11 had the organism detected in specimens obtained by bronchoscopy (negative predictive value, 39%). There were no clinical features that identified patients more likely to have a positive sputum examination. No additional treatable lung pathogens appeared to be missed by sputum examination. In this select population, examination of induced sputum establishes the diagnosis of P. carinii pneumonia in a significant proportion of patients, thereby decreasing the need for more invasive procedures.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Interaction of cromolyn and a muscarinic antagonist in inhibiting bronchial reactivity to sulfur dioxide and to eucapnic hyperpnea alone.

To determine whether the combination of an agent thought to inhibit mediator release (cromolyn) and an agent that inhibits parasympathetic pathways inhibits sulfur dioxide-induced bronchoconstriction more than either agent alone, we measured the bronchomotor response of 9 asthmatic subjects to inhalation of sulfur dioxide after treatment with cromolyn sodium (200 mg by spinhaler), with atropine sulfate (2.0 mg by nebulizer), and with the 2 drugs given together. Then, to determine whether the combination of cromolyn and a parasympathetic antagonist would similarly inhibit bronchoconstriction provoked by a different nonallergic stimulus, we measured the bronchomotor response of another group of asthmatic subjects to eucapnic hyperpnea of dry air at room temperature after treatment with cromolyn (200 mg), with ipratropium bromide (100 and 200 micrograms by metered-dose inhaler), and with cromolyn (200 mg) and ipratropium bromide (200 micrograms) given together. In both studies, we found that the combination treatment provided greater protection than that obtained with either agent alone. The concentration of sulfur dioxide required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and atropine (2.58 ppm, geometric mean) than after cromolyn alone (0.84 ppm), after atropine alone (0.78 ppm), or after placebo (0.43 ppm). Similarly, the rate of ventilation with dry air required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and ipratropium (106 +/- 22 L/min, mean +/- SD) than after cromolyn alone (65 +/- 19 L/min), after 200 micrograms of ipratropium alone (64 +/- 13 L/min), or after placebo (43 +/- 10 L/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Hydroxyurea inhibits airway hyperresponsiveness in guinea pigs by a granulocyte-independent mechanism.

Exposure of guinea pigs to toluene diisocyanate (TDI) causes an increase in airway responsiveness to inhaled acetylcholine. This increased airway responsiveness is temporally associated with an increase in polymorphonuclear leukocytes (PMN) in the tracheal wall. To determine whether PMN play a mechanistic role in this increase in acetylcholine responsiveness, we studied the effects of PMN depletion on this response with 2 different cytotoxic drugs, hydroxyurea and cyclophosphamide. Airway responsiveness was measured in untreated, hydroxyurea-treated, or cyclophosphamide-treated animals while they breathed spontaneously or during mechanical ventilation through a tracheostomy. In untreated animals, exposure to TDI caused a significant increase in airway responsiveness to acetylcholine for both spontaneously breathing and anesthetized and ventilated animals. This TDI-induced increase in airway responsiveness was associated with a significant influx of PMN into both the extravascular and intravascular trachea. Treatment with hydroxyurea, to reduce PMN counts in the bloodstream to less than 200/mm3, inhibited both the TDI-induced increase in airway responsiveness and the TDI-induced influx of PMN into the trachea of both spontaneously breathing and mechanically ventilated animals. In mechanically ventilated animals, treatment with cyclophosphamide, until PMN counts in the bloodstream were less than 200/mm3, also inhibited the influx of PMN into the trachea but did not inhibit the TDI-induced increase in airway responsiveness. These results suggest that PMN are not necessary for the TDI-induced increase in airway responsiveness and that hydroxyurea inhibits this effect by a mechanism other than PMN depletion.

Acetylcholine↗
PubMed1985

Effect of 0.25 ppm sulfur dioxide on airway resistance in freely breathing, heavily exercising, asthmatic subjects.

We sought to determine whether 0.25 ppm sulfur dioxide in filtered air causes bronchoconstriction when inhaled by freely breathing, heavily exercising, asthmatic subjects. Nineteen asthmatic volunteers exercised at 750 kilogram meters/min for 5 min in an exposure chamber that contained filtered air at ambient temperature and humidity or, on another day, filtered air plus 0.25 ppm sulfur dioxide. The order of exposure to sulfur dioxide and to filtered air alone was randomized, and the experiments were double-blinded. Specific airway resistance, measured by constant-volume, whole-body plethysmography, increased from 6.38 +/- 2.07 cm H2O X s (mean +/- SD) before exercise to 11.32 +/- 8.97 after exercise on days when subjects breathed filtered air alone and from 5.70 +/- 1.93 to 13.33 +/- 7.54 on days when subjects breathed 0.25 ppm sulfur dioxide in filtered air. The increase in specific airway resistance on days when subjects breathed 0.25 ppm sulfur dioxide was only slightly greater than on days when they breathed filtered air, but the difference was significant. To determine whether 0.25 ppm sulfur dioxide causes greater bronchoconstriction in asthmatic subjects exercising more vigorously, 9 subjects then repeated the experiment exercising at 1,000 instead of 750 kilogram meters/min. Specific airway resistance increased from 6.71 +/- 2.25 to 13.59 +/- 7.57 on days when subjects breathed filtered air alone and from 5.23 +/- 1.23 to 12.54 +/- 6.17 on days they breathed 0.25 ppm sulfur dioxide in filtered air. The increase in specific airway resistance on the 2 days was not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗
PubMed1985

Respiratory heat loss is not the sole stimulus for bronchoconstriction induced by isocapnic hyperpnea with dry air.

It is uncertain if respiratory heat loss or respiratory water loss is the stimulus for bronchoconstriction induced by isocapnic hyperpnea or exercise with dry air in subjects with asthma. We partially separated these 2 stimuli by having 18 subjects with asthma breathe dry air (0 mg/L water content) at increasing ventilations by isocapnic hyperpnea while we measured the increase in specific airway resistance (SRaw). The study was divided into 2 phases. In Phase 1, we used an apparatus with a single respiratory valve and evaluated the subjects' responses at 3 different inspired temperatures (-8.4, 20.5, and 39.4 degrees C). Seven of the subjects had esophageal catheters with 2 thermocouples in place to measure retrocardiac and retrotracheal temperatures. In this phase, we found that there were no significant differences in the ventilation required to cause a 100% increase in SRaw among the 3 different inspired temperatures (48.4 L/min, cold; 47.5 L/min, room temperature; 44.2 L/min, hot), even though the retrotracheal temperature fell more when the subjects breathed cold air at 40 L/min (2.1 degrees C) than when they breathed hot air (1.2 degrees C), suggesting greater airway cooling with the cold air. In Phase 2, in order to accurately measure inspired and exhaled temperatures and exhaled water content, we used 2 separate systems for delivering the inspired air and collecting the exhaled air at 2 different inspired temperatures (-21.4 and 38.9 degrees C). Again, we found that there was no significant difference in the ventilation required to cause a 100% increase in SRaw between the 2 different inspired temperatures (28.3 L/min, cold; 33.6 L/min, hot). When the subjects inhaled cold air, exhaled temperature was warmer than previously reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Aminophylline increases the toxicity but not the efficacy of an inhaled beta-adrenergic agonist in the treatment of acute exacerbations of asthma.

We studied 40 patients with acute exacerbations of asthma to determine the efficacy of a 3-h intravenous infusion of aminophylline in patients who were already being treated with an inhaled beta-adrenergic agonist (metaproterenol). Each patient was treated with inhaled metaproterenol at hourly intervals for 3 h. In addition, patients were randomly assigned to therapy with either intravenous aminophylline or placebo. Neither the patient nor the house officers and nurses caring for the patient knew whether aminophylline or placebo was given. The FEV1 improved continually throughout the study to a similar extent in both treatment groups, but the patients treated with aminophylline had significantly more adverse effects (p less than 0.025, Mann-Whitney). There was no apparent benefit from aminophylline even in patients who presented to the emergency room with severe airway obstruction (FEV1 less than 0.8L) or with plasma theophylline levels less than 10 mg/L. We conclude that intravenous aminophylline adds to the toxicity but not the efficacy of inhaled metaproterenol in the treatment of acute exacerbations of asthma.

Adolescent↗
PubMed1985

Effect of eucapnic hypoxia on bronchomotor tone and on the bronchomotor response to dry air in asthmatic subjects.

Because hypoxia has been shown to cause bronchoconstriction and to potentiate bronchomotor responsiveness in animals, we investigated whether hypoxia has similar effects in subjects with asthma. We measured specific airway resistance (SRaw; the mean of 5 sequential readings taken 30 s apart) before and immediately after each of 15 asthmatic subjects breathed a mixture of 8% O2 in N2 until hemoglobin saturation (SaO2; by ear oximetry) fell to 80% or less for at least 2 min. We maintained end-tidal CO2 at resting levels, the temperature of the inspirate at 22.0 +/- 1.1 degrees C, and the dew point at 18.5 +/- 1.6 degrees C (mean +/- SD). The SaO2 fell to 70 +/- 8%; minute ventilation rose to 28.4 +/- 8.5 L/min, and heart rate rose by 27 +/- 6 beats/min. The SRaw did not increase significantly in the group (baseline SRaw, 6.61 +/- 2.36; posthypoxia SRaw, 6.69 +/- 2.21 L X cm H2O/L/s) or in any subject. To determine if hypoxia increases bronchomotor responsiveness, we also compared the responses to eucapnic hyperpnea with dry air and with dry gas mixtures of 7 to 10% O2 in N2 in a randomized, double-blind sequence in 9 of the subjects. We measured SRaw in each subject before and after stepwise increases in minute ventilation, for 3 min at each level, until SRaw doubled or until the subject's maximal voluntary ventilation was achieved. The SaO2 fell to 82% or less at each level of ventilation with the hypoxic gas mixture. The 2 stimulus-response curves thus obtained did not differ in any subject.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Airway hyperresponsiveness and inflammation induced by toluene diisocyanate in guinea pigs.

We examined the changes in airway responsiveness to increasing doses of an acetylcholine aerosol in anesthetized and ventilated guinea pigs 2, 6, or 24 h after exposure to 2 ppm toluene diisocyanate (TDI) or 2 h after exposure to air or 1 ppm TDI. Pulmonary resistance (RL) after the animals inhaled a buffered saline aerosol was used as baseline and was similar for air and TDI groups. The concentration of acetylcholine calculated to cause a 200% increase in RL was significantly lower for animals studied at 2 h (0.68%) or at 6 h (0.77%), but not at 24 h (2.39%), after TDI than for air animals (3.07%). The increase in airway responsiveness in the TDI-exposed animals was associated with histologic changes in the trachea and intrapulmonary airways. Exposure to 2 ppm TDI caused a patchy loss of cilia, shedding of epithelial cells into the airway lumen, and an influx of inflammatory cells into the trachea and other airways. In the lamina propria of the trachea, the concentration of extravascular polymorphonuclear leukocytes (PMN) was 13- to 26-fold greater in animals studied 2 or 6 h after exposure to 2 ppm TDI or at 2 h after 1 ppm TDI than in animals exposed to air. The concentration of PMN in the epithelium was significantly increased only in animals examined 2 h after 2 ppm TDI. Exposure to TDI also caused an influx of eosinophils into the tracheal mucosa. This influx occurred later and was more persistent than the influx of PMN. These results indicate that a single exposure to TDI can cause an increase in airway responsiveness that is associated with epithelial injury and acute airway inflammation.

Acetylcholine↗
PubMed1984

Lack of bronchomotor response to up to 3 ppm formaldehyde in subjects with asthma.

A study was undertaken to determine whether exposure to concentrations of formaldehyde occasionally encountered in polluted indoor air would cause bronchoconstriction in subjects with mild asthma. In seven subjects the increase in specific airways resistance (SRaw) caused by inhalation of 1 ppm formaldehyde for 10 min was compared with the response caused by inhalation of formaldehyde-free air. Also, the increase in SRaw caused by inhalation of 1 and 3 ppm formaldehyde during moderate exercise for 10 min was compared with the response caused by inhalation of formaldehyde-free air during exercise for 10 min. Inhalation of formaldehyde at rest and during exercise did not cause a significant increase in SRaw in the subjects. It is concluded that brief exposure to these concentrations of formaldehyde, even in association with moderate exercise, is unlikely by itself to cause significant bronchoconstriction in most subjects with mild asthma.

Adolescent↗