Experimental models of asthma.
Explore the source record for details and available documents.
Airway Resistance↗
Biomedical subjects
A Wanner
Publications and source records attributed to A Wanner.
Role of ciliary motility in acute allergic mucociliary dysfunction.
The purpose of this investigation was to determine if abnormal ciliary function contributes to allergic mucociliary dysfunction. In conscious sheep with Ascaris suum hypersensitivity, ciliated cells were obtained with a cytology brush and tracheal mucous velocity (TMV) was determined before and serially for 2 h following antigen inhalation. The recovered cells (also containing mast cells) were suspended in a chamber, and ciliary activity was viewed microscopically and recorded on videotape for subsequent slow-motion analysis of ciliary beat frequency (CBF). One hour after A. suum challenge mean CBF (+/- SE) showed a slight increase from a base-line value of 630 +/- 16 to 716 +/- 30 beats/min (P less than 0.05) when mean TMV was decreased to 57% of base line (P less than 0.05). After 2 h, both mean CBF and TMV returned toward base line. Since possible in vivo actions of chemical mediators liberated by antigen challenge may have been lost after suspension of the brushed cells, we also assessed the effects of antigen on CBF in vitro. A. suum caused a dose-dependent increase in CBF that was blocked by cromolyn sodium. We conclude that 1) allergic mucociliary dysfunction is not caused by a decrease in CBF and 2) antigen-induced release of chemical mediators increases CBF.
Acute Disease↗
Characterization of H1- and H2-receptor function in pulmonary and systemic circulations of sheep.
We investigated the histamine H1- and H2-receptor function in the pulmonary and systemic circulations of sheep by in vivo and in vitro techniques. Combined H1 and H2 stimulation (by intravenous histamine) in vivo increased pulmonary vascular resistance (PVR) to 435% of base line and decreased systemic vascular resistance (SVR) to 49% of base line. Selective H2 stimulation (histamine after chlorpheniramine pretreatment) decreased PVR and SVR to 86 and 82% at base line, respectively, while selective H1 stimulation (histamine after metiamide pretreatment) increased PVR to 424% of base line and decreased SVR to 64% of base line. Combined H1- and H2-antagonist pretreatment completely blocked the effects of histamine on SVR, while PVR still decreased to 85% of base line, suggesting a mild "atypical" H2-receptor response in the pulmonary circulation under conditions of resting vascular tone. With increased pulmonary vascular tone (hypoxia), histamine decreased PVR to 55% (H1-antagonist pretreatment) and to 58% (combined H1- and H2-antagonist pretreatment) of posthypoxia values, respectively, demonstrating a marked atypical H2-receptor response. In vitro, both pulmonary arterial and venous strips showed a contractile dose-response to histamine, which was blocked by the H1-antagonist pyrilamine (mepyramine). In precontracted strips, both histamine and the H2-agonists (dimaprit and impromidine) elicited a relaxant response, which was neither blocked by H1-antagonist alone nor by combined H1- and H2-antagonists. We conclude that in sheep the histamine-induced pulmonary vasoconstrictor response is mediated by H1-receptors, while the pulmonary vasodepressor response is mediated by atypical H2-receptors. The systemic vasodepressor response is mediated by both H1- and typical H2-receptors.
Animals↗
Hypoxic pulmonary vasoconstriction in conscious sheep: role of mast cell degranulation.
We used pharmacologic and histologic techniques to investigate the role of mast cells in the mediation of hypoxic pulmonary vasoconstriction in conscious sheep. Breathing a hypoxic gas mixture (13%, 02, 87% nitrogen) caused hypoxic pulmonary vasoconstriction (HPV) with increases in mean pulmonary artery pressure and pulmonary vascular resistance by 97 and 90%, respectively. Intravenous pretreatment with the mast cell membrane stabilizing agent cromolyn sodium (3 mg/kg/min) completely blocked HPV, whereas the H1-histamine receptor antagonist chlorpheniramine, alone or in combination with the H2-receptor antagonist metiamide and the prostaglandin synthetase inhibitor indomethacin, failed to prevent HPV. Cromolyn sodium failed to modify the pulmonary pressor response to infusions of norepinephrine (alpha-agonist), tyramine (catecholamine-releasing agent), and histamine, indicating the specificity of cromolyn sodium action on the mast cells. Electromicroscopic studies of pulmonary perivascular mast cells showed that a 90-min exposure to the hypoxic gas mixture reduced the total number of granules per mast cell to 75% of control. This was blocked by cromolyn sodium pretreatment. We conclude that in conscious sheep], HP[V is initiated by the liberation of a mast cell product (other than histamine) that either directly or indirectly causes pulmonary vasoconstriction.
Animals↗
Airway responses to antigen challenge in allergic rhinitis and allergic asthma.
The density dependence of the maximum expiratory flow-volume curve, functional residual capacity (FRC), and specific airway conductance (SGaw) were determined before and during bronchial provocation with ragweed extract in 27 subjects with ragweed hypersensitivity and a history of either bronchial asthma (16 subjects) or allergic rhinitis (11 subjects). Mean baseline SGaw was significantly lower while mean volume of isoflow (Visov) and FrC were significantly higher in subjects with bronchial asthma. During antigen challenge, 10 of 16 subjects with bronchial asthma (63%) and five of 11 subjects with allergic rhinitis (45%) showed a greater than 35% decrease in SGaw ("reactors"): mean relative decreases in SGaw from baseline were 46% and 53%, respectively. The remaining subjects showed a less than 35% decrease in SGaw ("nonreactors") with mean relative decreases of 9% (allergic asthma) and 6% (allergic rhinitis). Mean Visov increased in all subjects with bronchial asthma and in eight of 11 subjects with allergic rhinitis. A significant increase in FRC (6%) was seen only in the "reactors" with bronchial asthma. Following antigen challenge, the beta adrenergic agonist, isoetharine, increased SGaw and decreased Visov. We conclude that in asymptomatic subjects with ragweed hypersensitivity, (1) central and peripheral airway function is more abnormal in subjects with bronchial asthma than in subjects with allergic rhinitis, (2) subjects of both groups show quantitatively and qualitatively comparable airway responses during antigen challenge with a decrease in SGaw or an increase in Visov, possibly representing increase in central and/or peripheral airflow resistance, respectively, (3) Visov may be a more sensitive indicator of airway response to antigen challenge than SGaw, and (4) the bronchodilator effects of a beta adrenergic agonist on antigen-induced bronchospasm are similar in both groups.
Adrenergic beta-Agonists↗
Differential effects of methacholine and antigen challenge on gas exchange in allergic subjects.
In order to better characterize the differential effects of nonspecific and specific (antigen) bronchial challenge on gas exchange, seven ragweed-sensitive subjects with a history of asthma underwent progressive inhalation challenge with methacholine and ragweed extract on two different days. For comparable severity of bronchospasm (mean specific airway conductance 0.05 sec-1cm-1H2O for methacholine and 0.06 sec-1cm-1H2O for ragweed), there was a greater decrease in mean arterial oxygen saturation after ragweed (4.7%) than after methacholine challenge (2.7%) (p less than 0.05). While this was not accompanied by differences in static lung volumes, the density-dependent index decreased by 19% after ragweed (p less than 0.001) but remained unchanged after methacholine challenge. These results suggest that a greater involvement of peripheral airways in the bronchospastic response is, at least in part, responsible for the greater decrease in arterial oxygen saturation after ragweed challenge.
Adult↗
Impaired tracheal mucus transport in allergic bronchoconstriction: effect of terbutaline pretreatment.
The transport velocity of mucus within the trachea, pulmonary resistance, and arterial blood gas composition were measured in intubated conscious sheep with Ascaris suum sensitivity before and during allergic bronchoconstriction. Inhalation of A. suum extract for 15 min increased mean pulmonary resistance significantly from 1.9 cm H2O . L-1 sec-1 to 5.1 cm H2O . L-1 sec-1 after 60 min and to 4.5 cm H2O . L-1 sec-1 after 120 min, while it decreased mean arterial PO2 from 85 to 59 and 53 mm Hg, respectively, without altering arterial PCO2 or pH. This was associated with a decrease in mean mucus velocity from 11.2 to 6.0 and 5.7 mm min-1, respectively. The decrease in mucus velocity was accompanied by endoscopically visible increases in the quantity of tracheal mucus. No alterations in mucus velocity or pulmonary resistance were observed in animals who inhaled a control antigen (ragweed) or breathed a mixture of 10% oxygen 90% nitrogen, which produced a mean arterial PO2 of 51 mm Hg. The administration of 0.25 mg terbutaline sulfate by subcutaneous injection prior to A. suum challenge prevented the changes in mucus velocity, pulmonary resistance, and arterial PO2. We conclude that the decreased mucus velocity in the trachea during antigen-induced bronchoconstriction in conscious sheep is related to the allergic response, and can be prevented by the subcutaneous administration of terbutaline sulfate, a beta adrenergic agonists. This suggests that the protective effect of terbutaline sulfate in antigen-induced bronchoconstriction includes the effect on the associated impairment of mucociliary function.
Animals↗
Differences in airway reactivity in normal and allergic sheep after exposure to sulfur dioxide.
The effect of breathing 5 ppm sulfur dioxide (SO2) on airway reactivity was studied in both normal and allergic conscious sheep. Allergic sheep were defined as animals in which inhalation of Ascaris suum extract resulted in bronchospasm as evidenced by an increase in mean pulmonary flow resistance (RL), hyperinflation, and a fall in dynamic compliance. Airway reactivity was assessed by measuring the increase of RL after 18 breaths of 0.25% carbachol (c), from an initial RL value obtained after 18 breaths of buffered saline (s) [RL(c-s)]. RL and RL(c-s) were determined prior to, immediately after, and 24 h after exposure to 5 ppm SO4 for 4 h. In both groups RL remained unchanged after SO2 exposure. Prior to exposure, RL(c-s) was not significantly different in seven normal (0.3 +/- 0.1) and seven allergic sheep [0.4 +/- 0.2 (SD) cmH2O X l-1 X s], and there was no significant change in RL (c-s) immediately after SO2 exposure in either group. Twenty-four h later, RL(c-s) RL(c-s) increased to 0.7 +/- 0.8 (P less than 0.2) in normal and to 1.8 +/- 0.9 cmH2O X l-1 X s (P less than 0.01) in allergic sheep. Because the increase in RL(c-s) after 24 h was greater (P less than 0.01) in allergic than in normal sheep, we conclude that SO2 exposure increased airway reactivity more in the former than in the latter.
Animals↗
Influence of lung inflation on the cross-sectional area of central airways in normals and in patients with lung disease.
The influence of lung inflation on the cross-sectional area of the trachea and main bronchi was investigated in 2 normal subjects, 2 patients with emphysema, and 1 patient with pulmonary fibrosis. Fiberoptic cinebronchoscopy was used to measure the cross-sectional area of the airways using calibrated small Teflon discs placed on the airway wall as reference. As an estimate of airway compliance at intermediate lung volumes, radial distensibility was defined as the change in cross-sectional area per change in airway pressure minus esophageal pressure divided by the cross-sectional area at functional residual capacity. Both in normal subjects and in patients with emphysema, the radial distensibility was larger in the trachea than in the main bronchi without differences between the right and left main bronchus. The area-pressure curves revealed alinearity and hysteresis in both groups with an increased distensibility in pulmonary emphysema. In a patient with pulmonary fibrosis, the distensibility was decreased by a factor of ten and the area-pressure curve was linear. These observations suggest altered static mechanics of extraparenchymal, intrathoracic airways in patients with pulmonary emphysema and fibrosis.
Adult↗
Abnormal mucociliary transport in allergic patients with antigen-induced bronchospasm: role of slow reacting substance of anaphylaxis.
We evaluated the possible role of slow reacting substance of anaphylaxis (SRS-A) in mediating mucociliary dysfunction in allergic asthma. In 6 asymptomatic nonsmokers with ragweed asthma, we measured specific airway conductance (SGaw) and tracheal mucous velocity (TMV) before and after bronchial challenge with ragweed extract, with or without pretreatment with 0.5% and 1% FPL-55712 (SRS-A antagonist). Mean baseline TMV was 8.9 mm/min (SD, 1.1). Placebo and FPL-55712 per se had no effect on TMV. With placebo pretreatment, the doses of ragweed extract that resulted in a decrease in SGaw by more than 35% from baseline, led to an immediate decrease in TMV to 74% of baseline (p less than 0.05), returning to baseline within 2 h. With 0.5% and 1% FPL-55712 pretreatment, doses of ragweed extract that resulted in a similar decrease in SGaw led to an increase in TMV to 130% and 126% of baseline (p less than 0.05), respectively, immediately after antigen challenge and returned to baseline 2 h postchallenge. Inhalation of 1% FPL-55712 immediately after antigen challenge prevented the decrease in TMV. These results indicate that (a) SRS-A liberated during airway anaphylaxis impairs mucous transport, and (b) the antigen-induced increase in TMV after pretreatment with an SRS-A antagonist may reflect a stimulatory effect of other chemical mediators of anaphylaxis.
Adolescent↗
Effect of pharmacologic agents on antigen-induced decreases in specific lung conductance in sheep.
The purpose of this investigation was to determine the primary mediators responsible for the decrease in specific lung conductance (SGL) after airway challenge with Ascaris suum antigen in allergic sheep. On different occasions, separated by 10 to 14 days, pulmonary resistance and thoracic gas volume were measured in 5 sheep with Ascaris suum hypersensitivity before and for 2 h after a standard inhalation challenge with this antigen. Initially and at the end of the study, inhalation challenge decreased mean SGL to 38 and 44% of baseline, respectively. Pretreatment by intravenous injection of the H1 receptor antagonist chlorpheniramine (2 mg/kg) completely prevented the antigen-induced decrease in SGL. Similar results were obtained with inhalation of the mediator release blocking agent, disodium cromoglycate (1 mg/kg), prior to antigen challenge. The decrease in SGL after inhalation challenge was not modified by pretreatment with the H2 receptor antagonist, metiamide (3 mg/kg), the anticholinergic agent, atropine (0.2 mg/kg), the prostaglandin synthetase inhibitor, indomethacin (2 mg/kg) by intravenous injection, or with inhalation of FPL-55712 (1% solution), an antagonist of slow-reacting substance of anaphylaxis (SRS-A). We concluded that during allergic bronchoconstriction in sheep (1) the decrease in SGL is mediated by histamine via H1 receptors, (2) other liberated or activated mediators including SRS-A do not decrease SGL, and (3) cholinergic reflex mechanisms are not involved in this response.
Airway Resistance↗
Tracheobronchial mucus: abnormalities related to asthma and its treatment.
The presence of mucociliary dysfunction in bronchial asthma is suggested by clinical observations and has been confirmed by pathologic and physiologic studies. Since mucociliary dysfunction may play a considerable role in the pathophysiology of bronchial asthma, currently available therapeutic measures which enhance mucous transport should be included in the treatment plan. It is expected that a better understanding of the underlying mechanisms will ultimately result in the development of more potent pharmacologic agents capable of improving abnormal mucociliary function.
Airway Obstruction↗
Alteration of tracheal mucociliary transport in airway disease. Effect of pharmacologic agents.
Explore the source record for details and available documents.
Animals↗
Mucociliary dysfunction in bronchial asthma.
The presence of mucociliary dysfunction in bronchial asthma is suggested by clinical observations and has been confirmed by pathologic and physiologic studies. Since mucociliary dysfunction may play a considerable role in the pathophysiology of bronchial asthma, currently available therapeutic measures which enhance mucous transport should be included in the treatment plan. It is expected that a better understanding of the underlying mechanisms will ultimately result in the development of more potent pharmacologic agents capable of improving abnormal mucociliary function.
Asthma↗
Sulfur dioxide induced airway hyperreactivity in allergic sheep.
The effects of a four-hour exposure (via a Plexiglas hood) to sulfur dioxide (SO2) on airway reactivity was studied in both normal and allergic conscious sheep. Allergic sheep were defined as animals in whom inhalation of Ascaris suum extract resulted in an increase in mean pulmonary flow resistance (RL). Airway reactivity (delta RL) was assessed by measuring the increase in RL after 18 breaths of 0.25% carbachol, from an initial value obtained after 18 breaths of buffered saline. RL and delta RL were determined prior to, immediately after and 24 hours following SO2 exposure in three groups of sheep: six normal sheep exposed to 5 ppm SO2 (group A); six normal sheep exposed to 10 ppm SO2 (group B) and seven allergic sheep exposed to 5 ppm SO2 (group C). RL was not affected by SO2 exposure in any group but both groups B and C showed increases in delta RL 24 hours after exposure. Since the increase in delta RL was greater in group C than in either groups A or B, we conclude that allergic sheep have enhanced susceptibility to the injurious airway effects of SO2.
Airway Resistance↗
Cardiopulmonary effects of short-term nitrogen dioxide exposure in conscious sheep.
Explore the source record for details and available documents.
Airway Resistance↗
Sensitivity of bronchoprovocation and tracheal mucous velocity in detecting airway responses to O3.
This study was undertaken to determine whether measurements of tracheal mucous velocity or airway reactivity to inhaled carbachol more sensitively detect airway effects of inhaled ozone (O3) in conscious sheep. Dose-response curves of mean pulmonary flow resistance (RL) to carbachol were obtained by measuring RL after five breaths of carbachol aerosol with stepwise increases in drug concentration. The animals then breathed 0.5 ppm O3 through an endotracheal tube for 2 h. The dose-response curves were repeated immediately after the 0.5 ppm O3 exposure and 24 h later. In the eight sheep studied, there were no significant alterations in base-line RL immediately after or 24 h after 0.5 ppm O3. Airway hyperreactivity was not apparent immediately after the sheep breathed 0.5 ppm O3, but it was evident 24 h later. In contrast, six sheep that breathed 0.5 ppm O3 in the same manner for 2 h did not show a significant depression in tracheal mucous velocity the same day or 24 h later. Exposure to 1 ppm O3 for 2 h resulted in airway hyperreactivity immediately after the exposure and elevated base-line RL 24 h later; 2 ppm O3 produced an increase in base-line RL immediately after exposure. We conclude that, in conscious sheep, airway hyperreactivity appears to be a more sensitive indicator of airway effects produced by short-term exposure to 0.5 ppm O3 than depression of tracheal mucous velocity.
Airway Resistance↗
Modification of hypoxic pulmonary vasoconstriction by antigen challenge in sensitized sheep.
Explore the source record for details and available documents.
Airway Resistance↗