Treatment of asthma.
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Adrenergic beta-Agonists↗
Biomedical subjects
K F Chung
Publications and source records attributed to K F Chung.
Histamine release and circulating cells after antigen inhalation in allergic dogs.
Histamine can be recovered from the blood of ragweed-sensitized dogs after aerosol antigen challenge, although its source is unknown. Neutrophils and eosinophils have been recovered from bronchoalveolar lavage fluid (BALF) obtained under identical conditions. We investigated the time course of changes in histamine levels in plasma and BALF taken from ragweed-sensitized dogs after aerosol challenge. Changes in the numbers of circulating neutrophils, eosinophils, lymphocytes, monocytes, and platelets were also studied. After 3 min, total pulmonary resistance (RL) was maximally increased and systolic blood pressure was maximally decreased. Histamine levels in plasma and BALF were increased and circulating eosinophils and neutrophils were decreased. After 15 min, platelet numbers were reduced. By 90 min, changes in RL, blood pressure, plasma and BALF histamine concentrations, and circulating neutrophils and eosinophils had returned to base-line values, but platelet numbers remained significantly decreased. Sham challenge caused no significant changes in any of these variables. Intravenous administration of histamine in doses large enough to attain plasma levels comparable with those achieved after aerosol antigen challenge resulted in no concomitant rise in BALF histamine levels. We conclude that antigen challenge in sensitized dogs causes increases in BALF and plasma histamine levels and is associated with a reduction in circulating neutrophils, eosinophils, and platelets. It is likely that antigen causes airway mast cells to release mediators that move down a concentration gradient from the airways to the pulmonary circulation.
Administration, Inhalation↗
Effect of platelet-activating factor on airway vascular permeability: possible mechanisms.
We studied the effects of the potent inflammatory mediator, platelet-activating factor (PAF), on vascular permeability in airways (and other tissues) of guinea pigs by measuring extravasation of circulating Evans blue dye. PAF caused a dose-dependent increase in vascular permeability. At 1 ng/kg iv, PAF caused an increase in Evans blue extravasation of 220% (P less than 0.05) in the trachea, with the greatest effect at a dose of 100 ng/kg (858%; P less than 0.01). Histamine (150 micrograms/kg iv) caused a 320% increase over base line in the trachea and 200% in main bronchi; this effect was equivalent to that induced by 10 ng/kg PAF in the trachea and 1 ng/kg in main bronchi. The duration of effect of PAF was greatest in main bronchi (less than 10 min). Platelet depletion with a cytotoxic antibody, or the cyclooxygenase inhibitor, indomethacin, or the cyclooxygenase-lipoxygenase inhibitor, BW 7556, did not affect the vascular permeability response to PAF. The PAF-receptor antagonist, BN 52063, inhibited Evans blue extravasation in the airways in a dose-dependent manner, with complete inhibition at 5 mg/kg. Thus PAF-induced airway vascular leakage is mediated by specific receptors but not by products of arachidonic acid metabolism or by platelets. Increased airway microvascular leakage induced by PAF may lead to plasma extravasation and airway edema, factors that may contribute to the airway narrowing and hyperresponsiveness induced by PAF.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
Hypotonic and isotonic aerosols increase bronchial reactivity in basenji-greyhound dogs.
Because basenji-greyhound dogs have greater bronchial reactivity to a range of inhaled stimuli than mongrel dogs do, and because bronchial hyperreactivity to nonspecific stimuli is characteristic of asthma, we asked whether basenji-greyhound dogs have greater bronchial reactivity to hypotonic and isotonic aerosols than mongrel dogs do. We assessed bronchial reactivity by measuring both the total pulmonary resistance and the bronchial response to an acetylcholine aerosol, before and after delivery of hypotonic and isotonic aerosols. Bronchial reactivity as measured by a change in total pulmonary resistance increased 9-fold after delivery of hypotonic and 5-fold after delivery of isotonic aerosols in 5 anesthetized basenji-greyhound dogs, but not in 3 similarly challenged mongrel dogs (p less than 0.01). Bronchial reactivity as measured by an increased bronchial response to acetylcholine aerosol increased 3-fold in basenji-greyhound dogs but not in mongrel dogs. Thus, hypotonic and isotonic aerosols increase bronchial reactivity in basenji-greyhound dogs. We also asked whether vagal or nonvagal pathways are involved in the increase in total pulmonary resistance induced by a hypotonic aerosol. Both vagal and nonvagal pathways appear to be involved, since blockade of the vagal pathway by intravenously administered atropine only partially inhibited the bronchoconstriction induced by a hypotonic aerosol (54%). Disodium cromoglycate, which inhibits vagal and nonvagal pathways, partially inhibited the bronchoconstriction (57%), but even in combination with atropine, did not completely inhibit it (68%). Our observations in basenji-greyhound dogs are similar to results in asthmatic subjects, suggesting that basenji-greyhound dogs are useful experimental animals in which to study the mechanisms by which hypotonic and isotonic aerosols increase bronchial reactivity.
Aerosols↗
Cutaneous mast cell heterogeneity: response to antigen in atopic dogs.
Because mast cells (MCs) in skin of atopic dogs are heterogeneous with respect to tissue fixation and staining properties, we determined the effect of antigen on each type of MC in vivo. Skin biopsies were done in anesthetized, ragweed-sensitized dogs before and at 1, 3, 6, and 24 hours after intradermal injections of ragweed antigen (n = 5) or glycerin diluent (n = 4). In each case, one biopsy specimen was fixed with formalin, and a second specimen from an adjacent abdominal site was fixed with basic lead acetate. In sections stained with Alcian blue, 49.7% more MCs (p less than 0.05) were detected in tissue fixed with basic lead acetate ("typical" plus "atypical" MCs: 2916 +/- 581/mm3; mean +/- SEM) than in tissue fixed with formalin ("typical" MCs: 1955 +/- 537/mm3). After antigen, the number of "typical" MCs detectable in tissue sections progressively decreased during the 24-hour period, whereas the number of "atypical" MCs was lowest at 1 hour and had increased at 24 hours. After diluent, MC numbers did not change significantly over time. A late-phase response (LPR), detected clinically as induration and edema, was present 6 hours after antigen in four of five dogs, but LPR was not detected after diluent. The size of LPR was correlated (r = 0.85; p less than 0.05) with the decrease in the number of "typical" MCs at 6 hours. We conclude that the response of the "typical" and "atypical" MC to antigen in vivo differs markedly. The "atypical" MCs participate in the early, acute response to antigen, and the "typical" MCs may be associated with the development of the LPR.
Animals↗
Role of inflammation in the hyperreactivity of the airways in asthma.
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Animals↗
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↗
Airway hyperresponsiveness induced by platelet-activating factor: role of thromboxane generation.
The effect of platelet-activating factor (acetyl glyceryl ether phosphorylcholine; PAF), a potent inflammatory mediator, on airway responsiveness was studied. In six dogs airway responsiveness was determined by measuring the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance (RL) by 5 cm H2O X L-1 X s, before and after inhalation of PAF (1 mg). PAF caused a 2.3-fold increase in RL (P less than .001) that lasted approximately 30 min. Airway hyperresponsiveness was maximal at 3 hr (mean 3.7-fold increase, P less than .001), persisted at 6 hr (P less than .005) and disappeared by 24 hr. Inhalation of 0.9% NaCl had no effect on RL or on responsiveness. PAF caused an 8-fold increase in neutrophil recovery in bronchoalveolar lavage fluid at 3 hr. OKY-046, a thromboxane synthetase inhibitor, inhibited PAF-induced bronchoconstriction and hyperresponsiveness but did not alter the increase in neutrophil recovery. We tested the specificity of the effect of OKY-046 on the release of cyclooxygenase products from canine neutrophils in vitro; OKY-046 suppressed PAF-induced generation of thromboxane and caused a small increase in prostaglandin F2 alpha release. The studies suggest that the airway hyperresponsiveness induced by PAF may depend on thromboxane generation.
Animals↗
Modulation of cholinergic neurotransmission in canine airways by thromboxane mimetic U46619.
We studied the effect of a thromboxane A2-mimetic, U46619, on the contractile responses of canine bronchial smooth muscle to cholinergic stimulation in vitro. U46619 (3 X 10(-10) M), at a concentration that did not cause contraction, enhanced the effect of electrical field stimulation at all frequencies; histamine (10(-7) M) and prostaglandin F2 alpha (10(-7) M) did not. U46619 (3 X 10(-10) M) did not affect methacholine-induced contractions. U46619 may therefore increase the prejunctional release of acetylcholine.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
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↗
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↗
Significance of thromboxane generation in ozone-induced airway hyperresponsiveness in dogs.
To determine whether thromboxane A2 may be involved in ozone (O3)-induced airway hyperresponsiveness, we studied the effect of a thromboxane synthase inhibitor (OKY-046, 100 micrograms X kg-1 X min-1 iv) in five dogs exposed to O3. Airway responsiveness was assessed by determining the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance by 5 cmH2O X l-1 X s. O3 (3 ppm) increased airway responsiveness as demonstrated by a decrease in acetylcholine provocative concentration from 2.42 (geometric SEM = 1.64) to 0.14 mg/ml (geometric SEM = 1.30). OKY-046 significantly inhibited this effect without altering pre-O3 responsiveness or the O3-induced increase in neutrophils and airway epithelial cells in bronchoalveolar lavage fluid. To further examine the role of thromboxane A2, we studied the effect of a thromboxane A2 mimetic, U-46619, on airway responsiveness in five additional dogs. U-46619 in subthreshold doses (i.e., insufficient to increase base-line pulmonary resistance) caused a fourfold increase in airway responsiveness to acetylcholine. Subthreshold doses of histamine had no effect. These results suggest that thromboxane A2 may be an important mediator of O3-induced airway hyperresponsiveness.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Prostaglandin F2 alpha increases responsiveness of pulmonary airways in dogs.
We studied the effect of prostaglandin F2 alpha (PGF2 alpha) on the responsiveness of pulmonary airways in dogs. Airway responsiveness was assessed by determining the bronchoconstrictor response to increasing concentrations of acetylcholine aerosol delivered to the airways. In each of five dogs, we determined responsiveness during treatment with physiologic saline, histamine, or PGF2 alpha aerosols. The doses of histamine and PGF2 alpha were determined by establishing the largest dose of each which could be given to the dog without causing bronchoconstriction (subthreshold doses). We found that airway responsiveness was not significantly different during histamine treatment than after saline, however, responsiveness increased during treatment with PGF2 alpha. In addition, the hyperresponsiveness induced by PGF2 alpha was prevented by pretreatment with the ganglion blocking drug hexamethonium (5 mg/kg given intravenously). The results show that PGF2 alpha specifically increases the responsiveness of pulmonary airways in doses that do not cause bronchoconstriction, and suggest that the hyperresponsiveness involves a neural mechanism such as increased responsiveness of airway sensory nerves.
Acetylcholine↗
Methacholine dose-response curves in normal and asthmatic man: effect of starting conductance and pharmacological antagonism.
The bronchial response of 11 normal and ten stable asthmatic subjects to increasing concentrations of methacholine aerosol was assessed by serial measurements of specific airways conductance (sGaw) in a body plethysmograph. Cumulative log dose-response curves were constructed. The threshold provocative dose of methacholine needed to cause a 35% fall in starting sGaw ( PD35 ) and the steepest slope of the response were measured from each curve. On separate days subjects were premedicated with 0.9% NaCl solution (control) in duplicate, chlorpheniramine, salbutamol and atropine, the last-named at two different doses, one twice the other. Asthmatic subjects had a lower mean PD35 and a lower mean slope than normal subjects. Pretreatment with salbutamol resulted in a greater increase in sGaw than after atropine but caused a smaller increase in PD35 in both groups. There was a dose-dependent increase in PD35 after the two doses of atropine, but no significant difference in bronchodilatation between doses. Mean steepest slope approximately doubled in these three sets of challenges. Chlorpheniramine caused a small degree of bronchodilatation and there was a non-significant increase in mean PD35 and in mean steepest slope in both normal and asthmatic groups. There was a positive linear correlation between starting sGaw and steepest slope in each group of premedicated challenges, such that when sGaw was high, either spontaneously or due to bronchodilatation, the slope was steeper. We conclude that increases in PD35 to methacholine after antagonist drugs are predominantly the result of pharmacological antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effect of prior bronchoconstriction on the airway response to histamine in normal subjects.
We have examined the effect of prior bronchoconstriction on the bronchial responsiveness to inhaled histamine in nine normal subjects. The airway response to increasing concentrations of histamine aerosol was assessed by measurement of specific airways conductance (sGaw) in a body plethysmograph. The threshold provocative dose of histamine needed to cause a 35% fall in starting sGaw (PD35) and the steepest slope of the response were measured from cumulative log dose response curves. Histamine challenges were performed in duplicate after premedication with 0.9% sodium chloride (control) or methacholine aerosol on separate days. The mean starting sGaw did not change significantly after inhalation of 0.9% sodium chloride but methacholine caused a mean reduction in sGaw of 42%. Mean control PD35 values did not differ significantly from mean PD35 values after methacholine. The mean steepest slope of the response after methacoline was 47% lower than the mean control value. There was a significant linear relationship between starting sGaw and the steepest slope for the control and for the methacholine premedicated challenges. The reduction in slope after methacholine was accounted for by the fall in starting sGaw. Because histamine PD35 was not altered by prior bronchoconstriction, it is concluded that the bronchial hyperresponsiveness of asthmatic subjects to non-specific bronchoconstrictor stimuli is unlikely to be a direct consequence of their low starting airway calibre.
Adult↗
Acromegaly and hyperprolactinemia in McCune-Albright syndrome. Evidence of hypothalamic dysfunction.
In a 21-year-old woman with McCune-Albright syndrome, acromegaly and hyperprolactinemia with hypopituitarism developed secondary to a large pituitary tumor. Bromocriptine suppressed the secretion of growth hormone and prolactin, with a reduction in tumor size. However, at the age of 8, she already showed evidence of biochemical acromegaly, with a paradoxical rise of growth hormone levels during two glucose tolerance tests, in the presence of a radiologically normal pituitary fossa. These data support the hypothesis that long-standing hypothalamic stimulation may have been responsible for the later development of a pituitary tumor.
Acromegaly↗
Mechanisms of airway narrowing in acute pulmonary oedema in dogs: influence of the vagus and lung volume.
In spontaneously breathing dogs (n = 8), maintained in the upright position, bronchial luminal diameter was measured from tantalum bronchograms. Changes in total intrathoracic lung volume were measured from radiographs taken at functional residual capacity (FRCR). With cooling of the cervical vagi to 0-4 degrees C mean bronchial diameter increased to 117 +/- 15 (SD)% of baseline diameter and FRCR increased to 113 +/- 16 of baseline volumes respectively. There was a significant correlation between changes in FRCR and bronchial diameter. After the vagi were rewarmed, pulmonary oedema was induced by rapid intravenous infusion of Hartmann's solution. Bronchi narrowed to a mean of 86 +/- 9% of baseline calibre and FRCR decreased (mean = 95 +/- 15%). With vagotomy bronchial diameter increased (mean = 102 +/- 12% of baseline diameter) but FRCR did not change significantly. Excluding one dog with gross oedema, changes in bronchial diameter due to oedema correlated positively with changes in FRCR; after vagotomy the relationship between diameter and FRCR was similar to that seen after vagal cooling in the baseline state, though individual values were lower. The shift in the diameter-FRCR relationship with vagotomy demonstrates that the direct bronchoconstrictor effect of the vagus is approximately doubled in the presence of pulmonary oedema. Bronchial and peribronchial oedema does not appear to directly narrow the bronchial lumen.
Animals↗
Suppression of prolonged fever during treatment of pulmonary tuberculosis: importance of using twice versus single daily dose of prednisolone.
We describe the clinical course of a patient with extensive pulmonary tuberculosis, in whom fever persisted despite adequate anti-tuberculous and broad-spectrum antibiotic treatment. A once daily morning dose of prednisolone failed to suppress the fever, but a twice daily regime was successful.
Drug Administration Schedule↗