Antigen-induced Bronchoconstriction Research Articles

Effects of chemical mediators of anaphylaxis on ciliary function

We assessed the effects of selected chemical mediators of anaphylaxis on CBF in vitro. Ciliated epithelial cells were obtained from the trachea of conscious sheep with a cytology brush and suspended in a perfusion chamber containing KH. Ciliary activity was viewed microscopically and recorded on videotape for subsequent slow-motion analysis of CBF. Prostaglandin E 1 (10 −8M to 10 −6M), prostaglandin E 2 (10 −10M to 10 −6M), and leukotriene-C 4 (10 −8M) increased CBF between 7% and 33%. Histamine caused ciliostimulation only at the relatively high concentrations above 10 −5M (7% increase in CBF), whereas prostaglandin F 2α (10 −10M and 10 −6M) was without effect. In no preparation was ciliary discoordination observed. These findings indicate that several chemical mediators of anaphylaxis stimulate CBF and that the previously described impairment of mucociliary transport in stable allergic asthma or antigen-induced bronchoconstriction is probably not caused by a primary alteration of ciliary function.

The effects of nifedipine and verapamil on antigen-induced bronchoconstriction in dogs

The effects of calcium channel blockers, nifedipine and verapamil (i.v. and aerosol), were investigated in beagle dogs natively allergic to Ascaris suum antigen. Control exposures to an aerosol of Ascaris antigen provoked significant bronchopulmonary changes, i.e., increases in pulmonary resistance (R L) and decreases in dynamic lung compliance (C DYN). Pretreatment with either nifedipine or verapamil (200 μg/kg, i.v.) provided significant inhibition in the R L responses to Ascaris antigen (P < 0.015) while neither agent significantly affected C DYN changes. When administered as an aerosol, verapamil (1.0%; 10 breaths) significantly inhibited both the R L and C DYN responses to Ascaris antigen ( P < 0.05), whereas a similar concentration of nifedipine was without effect. Resting basal levels of R L and C DYN were unaffected by either the i.v. route or by aerosols of either nifedipine or verapamil. These results suggest that calcium channel blockers may have beneficial effects against allergen-provoked bronchoconstriction; however, differences appear to exist in the choice of agent, route of administration and site of action.

Exercise-induced late asthmatic reactions with neutrophil chemotactic activity.

Two adults and 13 children with exercise-induced asthma had both immediate and late reductions in forced expiratory volume in one second (FEV1) after treadmill exercise. The late reactions developed 4 to 10 hours after exercise and in each instance were associated with wheezing or chest tightness (or both). Increases in neutrophil chemotactic activity, measured in the 2 adults and in 11 of the children, accompanied the reductions in FEV1 in all these subjects. In contrast, four other adults with only an immediate fall in FEV1 after exercise had only an initial elevation in neutrophil chemotactic activity, with no subsequent increase for the remaining 24-hour period. The agent responsible for the neutrophil chemotactic activity released during exercise-induced late reactions appeared to be identical to that released during immediate reactions. These observations suggest that some patients with exercise-induced asthma have late reactions that, as in the case of antigen-induced bronchoconstriction, are accompanied by the release of neutrophil chemotactic activity.

Effects of nifedipine on antigen-induced bronchoconstriction.

We have investigated the effects of the calcium antagonist nifedipine on antigen-induced bronchoconstriction in vivo and in vitro. Eight grass-pollen-sensitive asthmatics were given either nifedipine (20 mg sublingually) or placebo 30 min before antigen challenge. The fall in forced expiratory volume in one second after pretreatment with placebo was 42.8 +/- 10.1%. After nifedipine this fall was significantly reduced to 26.5 +/- 11.7% (p less than 0.005). Two in vitro models of allergic asthma have been studied: actively sensitized guinea pig tracheal strips (GPT) and passively sensitized human bronchial muscle (HBM). Contraction of GPT by acetylcholine, histamine, and antigen challenge was unaffected by nifedipine 10(-4)M. Contraction of HBM by acetylcholine, histamine and grass pollen antigen challenge was significantly reduced by nifedipine 10(-4)M and 10(-6)M. The magnitude of the reduction in contraction to antigen challenge was comparable to the inhibition of acetylcholine and histamine responses. It would appear most likely that nifedipine exerts its effect mainly on bronchial muscle contractility rather than by stabilizing mast cells.

Effects of inhibitors of anaphylactic mediators in two models of bronchial anaphylaxis in anaesthetized guinea-pigs.

1 The effects of pretreatment with various inhibitors of anaphylactic mediators on antigen-induced bronchoconstriction were studied in anaesthetized guinea-pigs, actively sensitized according to two different regimens (one producing IgE- and IgG-like antibodies and the other producing exclusively IgG antibodies).2 The phospholipase A(2)-inhibitors mepacrine and p-bromphenacylbromide caused a dose-dependent inhibition of the antigen-induced bronchoconstriction in guinea-pigs sensitized to produce both IgE and IgG antibodies. No effect was seen in those sensitized to produce only IgG antibodies.3 In both models indomethacin pretreatment led to an increased anaphylactic bronchoreactivity, whereas mepyramine and FPL 55712 reduced it.4 BW 755C significantly reduced antigen-induced bronchoconstriction in guinea-pigs sensitized to produce both IgE and IgG antibodies. In this model, the residual bronchoconstriction evident after combined pretreatment with indomethacin and mepyramine was prevented by additional pretreatment with mepacrine, FPL 55712 or budesonide.5 Arachidonic acid given intravenously caused a marked bronchoconstriction that was prevented by indomethacin but not by budesonide, FPL 55712 or p-bromphenacylbromide.6 Although the same pattern of anaphylactic mediators is released in the two models of anaphylactic bronchoconstriction, a different activation mechanism is indicated by the results obtained with phospholipase A(2) inhibitors.

Exercise-induced release of histamine and neutrophil chemotactic factor in atopic asthmatics

Concentrations of plasma histamine and serum neutrophil chemotactic factor (NCF) were measured in seven atopic asthmatics who developed exercise-induced asthma (EIA) after a treadmill task. The results were compared with those obtained after inhalation of specific antigen or methacholine. Plasma histamine concentrations were measured with a novel double-isotope radiometric assay, and NCF was identified by its elution in the void volume fractions of Sephadex G-200 and as a single peak of activity at approximately 0.20 molar NaCl after anion exchange chromatography on diethylaminoethyl-Sephacel (pH 7.8). After exercise or antigen challenge, the time courses of appearance of both mediators were virtually identical and accompanied the increase in airways obstruction. There was a statistically significant correlation between the concentrations of histamine or NCF and the magnitude of airflow obstruction after exercise and antigen challenge. This suggested that there may be a direct association between mediator release and EIA or antigen-induced bronchoconstriction. In contrast, there were no significant elevations in circulating histamine and NC'F after inhalation of methacholine, at concentrations giving a fall in FEV 1 comparable to that induced by exercise or antigen. The prior administration of cromolyn to three asthmatics inhibited both their EIA and the release of histamine and NCF. When four asthmatics were exercised for periods of 1, 3, and 6 min, the release of NCF and fall in peak expiratory flow rate were directly related to the duration of the exercise. The rise of NCF activity in subjects with EIA was fivefold greater than that observed in asthmatics who did not experience airways obstruction when subjected to the same exercise task. These results provide further evidence that mediators of hypersensitivity are released during EIA.

The action of disodium cromoglycate on allergen-induced bronchoconstriction.

The influence of DSCG administered to the upper and lower area of the air-conducting system on antigen-induced bronchoconstriction was studied in 34 dogs. In high doses DSCG administered to the upper airtract blocked bronchoconstriction and histamine release induced from the lower airways. Bronchoconstriction and histamine release originating from the upper airtract were not completely blocked by this kind of drug administration. Effects were differently strong in the individual animals. High doses of DSCG, administered to the lower airways, showed significant effect on bronchoconstriction originating from the lower airways. There was some yet nonsignificant effect on histamine release. Inhibition of respiratory activity without parallel inhibition of histamine release might suggest that plasma histamine concentration does not reflect the mode of action of DSCG in antigen-induced bronchoconstriction.

Thromboxane A 2 mediated bronchoconstriction in the anesthetized guinea pig

Arachidonic acid-induced platelet aggregation has been shown to be selectively antagonized by the thromboxane A 2 synthetase inhibitor SQ 80,338 or by the thromboxane A 2 receptor antagonist SQ 24,775. Experiments were done to see what effect these two compounds would have on the bronchoconstrictor response to various agents in the anesthetized guinea pig. Increases in pulmonary resistance and decreases in dynamic compliance were taken as an index of bronchostriction. Both SQ 80,338 (0.3–10.0 mg/kg) and SQ 24,775 (0.1–1.0 mg/kg) administered i.v. caused dose-related inhibitions of arachidonate-induced bronchoconstriction. SQ 80,338 (3.0 and 10.0 mg/kg) also inhibited bradykinin-induced bronchoconstriction in the presence of β-adrenergic blockade. These same doses of SQ 80,338 and SQ 24,775 did not alter either histamine- or antigen-induced bronchoconstriction. SQ 80,338 (10.0 μg/ml) prevented arachidonate-induced release of TXA 2 from the isolated perfused guinea pig lung while SQ 24,775 (1.0 μg/ml) antagonized the contraction of the isolated rat aorta induced by 9,11,AZO-PGH 2. These results suggest that both arachidonate- and bradykinin-induced bronchoconstriction are mediated through the generation of TXA 2, while histamine- and antigen-induced bronchoconstriction are not.

Protective effects of the glucocorticoid, budesonide, on lung anaphylaxis in actively sensitized guinea-pigs: inhibition of IgE-but not of IgG-mediated anaphylaxis.

1 The effect of glucocorticoid pretreatment on antigen-induced bronchoconstriction was studied in guinea-pigs actively sensitized to two different ovalbumin regiments (one producing IgE- and IgG-like antibodies and the other exclusively IgG-like antibodies). 2 Budesonide (50 mg/kg) and hydrocortisone (50 mg/kg) given as one intraperitoneal injection 15-20 h before and anaphylactic tests or as two consecutive intraperitoneal injections 5 and 6 days before, led to a decreased bronchial capacity. In this respect glucocorticoid pretreatment was effective only in guinea-pigs sensitized to produce both IgE-like and IgG-like antibodies. 3 Budesonide pretreatment also reduced the capacity of anaphylactically-challenged chopped lung tissue to release histamine in guinea-pigs sensitized to produce both IgE- and IgG-like antibodies. 4 Budesonide pretreatment did not change the levels of circulating IgG1a and IgE-like homocytotropic antibodies as measured by passive cutaneous anaphylaxis; nor did it affect histamine or methacholine-induced bronchoconstriction in vivo or the capacity of histamine or methacholine to contract the guinea-pig isolated trachea preparation of the isoprenaline-induced relaxation of this preparation. 5 The selective inhibitory effects of budesonide and hydrocortisone on IgE-mediated but not IgG-mediated anaphylaxis and the relevance to human atopic disease are discussed.

Antigen-induced bronchial anaphylaxis in actively sensitized guinea-pigs: effect of long-term treatment with sodium cromoglycate and aminophylline.

1 The effects of long-term treatment with sodium cromoglycate (SCG) and aminophylline on antigen-induced bronchoconstriction have been studied in guinea-pigs actively sensitized according to two different regimens (one producing IgE- and IgG-like antibodies and the other producing exclusively IgG-like antibodies). 2 Treatment for three weeks with SCG (10 mg/kg) and aminophylline (10, 30 or 60 mg/kg) led to a decreased bronchial response capacity which persisted even three days after treatment ceased. In this respect SCG was effective only in guinea-pigs sensitized to produce at least partly IgE-like antibodies; aminophylline was effective in guinea-pigs sensitized to produce both IgE and/or IgG antibodies. 3 The results in vivo with SCG were reflected in vitro by a reduced capacity of chopped lung tissue to release histamine at antigen challenge; lungs from animals treated with aminophylline did not show reduced histamine releasing capacity. 4 Acute treatment with atropine was shown to reduce significantly the antigen-induced bronchial contraction in guinea-pigs sensitized to produce both IgE- and IgG-antibodies. No effect of atropine was seen on an IgG-mediated anaphylaxis. 5 Increased reactivity to methacholine but not to histamine was seen in guinea-pigs sensitized to produce both IgG- and IgE-antibodies. Long-term treatment with SCG did not affect this hyperreactivity to methacholine. 6 Decreased reactivity to isoprenaline was found in isolated tracheae taken from guinea-pigs sensitized to produce both IgE- and IgG-like antibodies compared to unsensitized guinea-pigs. Long-term treatment with SCG, but not with aminophylline, reversed this decreased reactivity.

Platelet Activation in Antigen-Induced Bronchoconstriction

Platelet Activation in Antigen-Induced Bronchoconstriction

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 H 2O · L −1 sec −1 to 5.1 cm H 2O · L −1 sec −1 after 60 min and to 4.5 cm H 2O · L −1 sec −1 after 120 min, while it decreased mean arterial P O 2 from 85 to 59 and 53 mm Hg, respectively, without altering arterial P CO 2 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 P O 2 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 P O 2 . 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 agonist. This suggests that the protective effect of terbutaline sulfate in antigen-induced bronchoconstriction includes the effect on the associated impairment of mucociliary function.

Basenji-Greyhound dog model of asthma: influence of atropine on antigen-induced bronchoconstriction.

To test the relative importance of cholinergic effects on the Basenji-Greyhound (BG) model of asthma, we administered Ascaris antigen to Ascaris-sensitive BG dogs without other treatment, and following intravenous atropine. Pulmonary resistance (RL) increased from 1.4 +/- 0.43 cmH2O . l-1 . s (mean + SE) to 26.0 +/- 5.21 after Ascaris antigen exposure in seven untreated dogs. In the same dogs pretreated with 0.2 mg/kg atropine, RL increased from 1.5 +/- 0.31 to 18 +/- 5.00. Atropine 0.4 and 1.0 mg/kg did not result in increased protection. Although 0.2 mg/kg atropine markedly inhibited the airway responses to both inhaled citric acid and methacholine, it only slightly prevented antigen-induced airway constriction. We conclude that in BG dogs, cholinergic pathways elicit bronchomotor responses to irritants but that the major component of antigen-induced bronchoconstriction is not cholinergically mediated.

Ro 21-7634, a new antiallergic agent with potent oral activity.

Ro 21-7634 was examined for oral antiallergic activity in two in vivo models commonly used to evaluate antiallergics. In the rat PCA test, this drug had an oral ID50 of 1.14 mg/kg and was found to be more potent than several other antiallergics including Disodium Cromoglycate (cromoglycate), Oxatomide, Doxanthrazole, Xanoxate, 2,6-bis (ethyoxyoxalylamino) pyridine, PRD-92-EA and M + B 22,948. In contrast to cromoglycate, Ro 21-7634 was found to be an orally active inhibitor of antigen-induced broncho-constriction in passively sensitized rats (ID50 = 0.2 mg/kg). In addition, Ro 21-7634 inhibited antigen-induced histamine release in an in vivo passive peritoneal anaphylaxis test system, following intraperitoneal administration. Ro 21-7634 demonstrated no end organ antagonism toward histamine, metacholine or serotonin in the guinea pig.

Lidocaine Aerosols Do Not Prevent Allergic Bronchoconstriction

To test the effectiveness of local anesthetic aerosols in asthma, we compared the protection afforded by lidocaine and saline aerosols to bronchoconstriction provoked by inhalation of Ascaris antigen aerosols in five previously sensitized, anesthetized Basenji-Greyhound, crossbred dogs. Pulmonary resistance (RL) was determined by the method of Von Neergaard and Wirz, and blood lidocaine levels were determined by gas chromatography. Lidocaine, 4%, was administered as an aerosol for 10 minutes before challenge with Ascaris antigen and again during the 10-minute challenge with Ascaris antigen. Lidocaine aerosols frequently elicited a slight increase in RL before antigen challenge, whereas saline aerosols did not alter RL. Despite a large dose (approximately 10 mg/kg), which produced blood levels of 0.6 to 3.3 micrograms/ml, lidocaine afforded no protection against antigen challenge: RL increased from a control mean of 4.2 +/- 1.7 (SEM) cm H2O/liters/sec to 26.9 +/- 9.3 after challenge in lidocaine-treated dogs, and from 2.9 +/- 0.6 to 22.8 +/- 5.1 in saline-treated dogs. In contrast, lidocaine aerosols prevented the 7-fold increase in RL elicited by challenge with citric acid aerosols, demonstrating an adequate block of irritant reflexes. The failure of lidocaine aerosols to protect against antigen-induced bronchoconstriction indicates that the concentrations achieved in lung by this route are inadequate to relax smooth muscle directly.

The site of action of a beta 2-receptor stimulating drug (Fenoterol) on antigen-induced bronchoconstriction.

The influence of Fenoterol administered to the upper and lower area of the air conducting system on antigen-induced bronchoconstriction was studied in 60 dogs. In small doses, Fenoterol administered to the upper airways blocked bronchoconstriction by antigen applied to upper but not to lower airways. The intravenous administration of the same dose was without effect. In large doses, Fenoterol blocked bronchoconstriction induced at both sites. Application of both doses of Fenoterol to lower airways blocked bronchoconstriction induced at both sites and was more effective than intravenous treatment.

Prevention of antigen-induced bronchoconstriction by lodoxamide ethyl, a new orally active antiallergic drug

Lodoxamide ethyl, an orally active drug with pharmacologic activity similar to that of cromolyn sodium, blocks passive cutaneous anaphylaxis (PCA) in rats and antigen-induced bronchoconstriction in guinea pigs and monkeys. Its effectiveness in preventing antigen-induced airway obstruction was studied in 12 asymptomatic asthmatic adults with immediate skin test sensitivity to ragweed, Alternaria, or animal dander. The dose required to reduce the forced expiratory volume in 1 sec (FEV 1 ) by 20% (PD 20 ) was determined by dosimeter bronchoprovocation challenge with the appropriate antigen. At 1-wk intervals each subject received either placebo or 1, 3, or 10 mg drug in a randomized, double-blind fashion 30 min prior to starting bronchoprovocation challenge. On average, 1 mg increased the PD 20 fivefold, 3 mg about sixfold, and 10 mg about 27-fold. Dose-related side effects began 10 min after drug and lasted up to 40 min. Thus the oral administration of lodoxamide ethyl was effective in preventing antigen-induced bronchoconstriction, and both the beneficial effects and side effects are dose related.

Effect of lodoxamide ethyl on allergy skin tests

Lodoxamide ethyl is a new cromolyn-like drug which prevents antigen-induced mediator release from mast cells and antigen-induced bronchoconstriction in sensitive animals and man. The purpose of this study was to determine the effect of a single administration of lodoxamide ethyl on allergy skin tests. The effect of this drug on allergy skin testing was studied in a double-blind design on ten adult subjects allergic to ragweed. Serial end-point titrations with short ragweed extract and with histamine were performed after a placebo and 1- and 3-mg capsules of lodoxamide ethyl. The immediate wheal-and-flare responses as well as the late allergic reaction were recorded. No statistically significant difference was found between lodoxamide ethyl and placebo in the suppression of the allergen-induced immediate wheal-and-flare response or the late allergic reaction. Furthermore, 1 and 3 mg of oral lodoxamide ethyl did not inhibit the histamine-induced cutaneous reactions.

Influence of antigen challenge on density dependence of maximal expiratory flow and nitrogen washout curves in extrinsic bronchial asthma.

In 14 nonsmokers with extrinsic bronchial asthma, static lung volumes, FEV 1.0, specific conductance, and maximal expiratory flow rates breathing air and a 80% He-20% O2 mixture were measured before and after antigen-induced bronchoconstriction. In 9 of these subjects, nitrogen washout curves after a VC breath of oxygen were obtained with determination of the slope of phase III, the height of phase IV and the closing capacity. Two subjects were retested once and three times, respectively, with different antigens. Density dependence of the maximal expiratory flow (ΔVmax 50 > 20%) was found in 78% pre- and 39% postprovocation. In the He responders after challenge, the height of phase IV increased, while in nonresponders after challenge the height of phase IV decreased. The results suggest that the major site of flow limitation in acute antigen-induced asthmatic attacks might be inter- and intra-individually located predominantly in central or peripheral airways depending on the host’s reaction to the antigen used for challenge.

The Role of Upper Airways in Antigen-Induced Bronchoconstriction

The bronchoconstrictor effect of antigen was tested in 15 dogs. The upper and the lower airways were sequently exposed through a specially confected endotracheal tube. The antigen was also generally administered through a mouth mask. Bronchoconstriction was induced after each kind of exposure. The results argue for reflex bronchoconstriction. The sensory receptors localized in the upper part of the airways are responsible for about 50% of antigen-induced bronchoconstriction. The decrease of PO2a was less marked following Ascaris suum extract aerosol administration to the upper part of the airways. Control measurements demonstrated the reproducibility of antigen-induced bronchoconstriction.