Allergen-induced Asthmatic Reactions Research Articles

Bronchoprotection by Olodaterol Is Synergistically Enhanced by Tiotropium in a Guinea Pig Model of Allergic Asthma

The novel once-daily β₂-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β₂-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergen-induced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.

Arginase Inhibition Protects against Allergen-induced Airway Obstruction, Hyperresponsiveness, and Inflammation

In a guinea pig model of allergic asthma, using perfused tracheal preparations ex vivo, we demonstrated that L-arginine limitation due to increased arginase activity underlies a deficiency of bronchodilating nitric oxide (NO) and airway hyperresponsiveness (AHR) after the allergen-induced early and late asthmatic reaction. Using the same animal model, we investigated the acute effects of the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) and of L-arginine on AHR after the early and late reaction in vivo. In addition, we investigated the protection of allergen-induced asthmatic reactions, AHR, and airway inflammation by pretreatment with the drug. Airway responsiveness to inhaled histamine was measured in permanently instrumented, freely moving guinea pigs sensitized to ovalbumin at 24 hours before allergen challenge and after the allergen-induced early and late asthmatic reactions by assessing histamine PC(100) (provocative concentration causing a 100% increase of pleural pressure) values. Inhaled ABH acutely reversed AHR to histamine after the early reaction from 4.77 +/- 0.56-fold to 2.04 +/- 0.34-fold (P < 0.001), and a tendency to inhibition was observed after the late reaction (from 1.95 +/- 0.56-fold to 1.56 +/- 0.47-fold, P < 0.10). Quantitatively similar results were obtained with inhaled l-arginine. Remarkably, after pretreatment with ABH a 33-fold higher dose of allergen was needed to induce airway obstruction (P < 0.01). Consequently, ABH inhalation 0.5 hour before and 8 hours after allergen challenge protected against the allergen-induced early and late asthmatic reactions, AHR and inflammatory cell infiltration. Inhalation of ABH or l-arginine acutely reverses allergen-induced AHR after the early and late asthmatic reaction, presumably by attenuating arginase-induced substrate deficiency to NO synthase in the airways. Moreover, ABH considerably reduces the airway sensitivity to inhaled allergen and protects against allergen-induced bronchial obstructive reactions, AHR, and airway inflammation. This is the first in vivo study indicating that arginase inhibitors may have therapeutic potential in allergic asthma.

A guinea pig model of acute and chronic asthma using permanently instrumented and unrestrained animals

To investigate mechanisms underlying allergen-induced asthmatic reactions, airway hyperresponsiveness and remodeling, we have developed a guinea pig model of acute and chronic asthma using unanesthetized, unrestrained animals. To measure airway function, ovalbumin (IgE)-sensitized animals are permanently instrumented with a balloon-catheter, which is implanted inside the pleural cavity and exposed at the neck of the animal. Via an external cannula, the balloon-catheter is connected to a pressure transducer, an amplifier, an A/D converter and a computer system, enabling on-line measurement of pleural pressure (P(pl))-closely correlating with airway resistance-for prolonged periods of time. Using aerosol inhalations, the method has been successfully applied to measure ovalbumin-induced early and late asthmatic reactions and airway hyperresponsiveness. Because airway function can be monitored repeatedly, intra-individual comparisons of airway responses (e.g., to study drug effects) are feasible. Moreover, this model is suitable to investigate chronic asthma and airway remodeling, which occurs after repeated allergen challenges. The protocol for establishing this model takes about 4 weeks.

Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions

Asthma is a chronic inflammatory disease with increasing incidence worldwide. Roflumilast is an oral, once-daily inhibitor of phosphodiesterase type 4 that prevents the breakdown of cyclic adenosine monophosphate levels, leading to inhibition of proinflammatory signaling. The objective of this study was to investigate the effects of repeated doses of 250 or 500 microg of roflumilast on asthmatic airway responses to allergen. Twenty-three patients with mild asthma with an FEV1 of 70% of predicted value or greater were enrolled in a randomized, double-blind, placebo-controlled, 3-period crossover study. Patients participated in 3 treatment periods (7-10 days) separated by washout periods (2-5 weeks). Patients received 250 microg of oral roflumilast, 500 microg of roflumilast, or placebo once daily. Allergen challenge was performed at the end of each treatment period, followed by FEV1 measurements over the ensuing 24 hours. Late asthmatic reactions (LARs) were reduced by 27% (P = .0110) and 43% (P = .0009) in patients treated with 250 and 500 microg of roflumilast, respectively, versus placebo. Roflumilast, 250 and 500 microg, also attenuated early asthmatic reactions by 25% (P = .0038) and 28% (P = .0046), although not to the same extent as LAR attenuation. Roflumilast was well tolerated. No serious adverse events or discontinuations caused by adverse events were reported. Once-daily oral roflumilast modestly attenuated early asthmatic reactions and, to a greater extent, LARs to allergen in patients with mild allergic asthma. Pronounced suppression of late responses in an allergen challenge model suggests that roflumilast might have anti-inflammatory activity, which could provide clinical efficacy in chronic inflammatory pulmonary diseases, such as asthma.

Effects of salbutamol and enantiomers on allergen-induced asthmatic reactions and airway hyperreactivity

Salbutamol consists of a racemic mixture of R- and S-salbutamol. R-salbutamol (levalbuterol) is the active bronchodilating enantiomer, whereas S-salbutamol is thought to be pharmacologically inactive or to exert adverse effects. This study evaluated the bronchoprotective effects of inhalation of therapeutically relevant doses of the racemate and individual enantiomers in guinea pigs. It was found that basal airway reactivity to histamine was similarly reduced 30 min after inhalation of equivalent doses of RS- and R-salbutamol; this protective effect disappeared within 3 h. Inhalation of RS- and R-salbutamol 30 min before and 5.5 h after allergen challenge suppressed allergen-induced airway hyperreactivity to histamine after the early and late asthmatic reaction, completely inhibiting the early asthmatic reaction and tending to reduce the development of the late asthmatic reaction. At 5 h after allergen challenge, the inhibition of airway hyperreactivity was more pronounced in animals treated with R-salbutamol compared to racemate-treated animals. Both basal airway reactivity and allergen-induced hyperreactivity were not affected by S-salbutamol. Inflammatory cell infiltration was not affected by the racemate or the individual enantiomers. In conclusion, inhalation of therapeutically relevant doses of R- and RS-salbutamol effectively suppress allergen-induced airway reactivity after the early and late asthmatic reactions, the R-enantiomer being slightly more potent with respect to early airway reactivity than the racemate. No adverse effects were observed for the S-enantiomer.

The usefulness of inflammatory markers in monitoring treatment responses in asthma

The usefulness of inflammatory markers in monitoring treatment responses in asthma

Role of histamine in allergen-induced asthmatic reactions, bronchial hyperreactivity and inflammation in unrestrained guinea pigs

In a new model using conscious, unrestrained and ovalbumin-sensitized guinea pigs, we investigated the effects of the selective histamine H 1 receptor antagonist, mepyramine, on the development of allergen-induced early and late asthmatic reactions, bronchial hyperreactivity and airway inflammation, having each animal as its own control. In guinea pigs responding to a first allergen exposure with an early as well as a late asthmatic reaction (82% of the animals) a second, identical, allergen provocation was performed, in the absence (control) or presence of 1 mg/ml mepyramine aerosol, inhaled for 10 min, 1 h before provocation. The mepyramine treatment significantly reduced both early and late asthamatic reactions and prevented the development of bronchial hyperreactivity to histamine and methacholine after both reactions. Examination of the bronchoalveolar lavage fluid 24 h after the second allergen provocation revealed a general reduction of inflammatory cells after mepyramine treatment. The results indicate that histamine, released during the early asthmatic reaction, contributes to the development of the late asthmatic reaction as well as of early and late bronchial hyperreactivity, possibly via an effect on airway inflammation.

P-487 - Allergen-induced asthmatic reactions with marked bronchial eosinophilia in guinea pigs and inhibitory effect of AL-3264, an anti-allergic agent.

P-487 - Allergen-induced asthmatic reactions with marked bronchial eosinophilia in guinea pigs and inhibitory effect of AL-3264, an anti-allergic agent.

Venous blood platelets decrease during allergen‐induced asthmatic reactions

To determine whether circulating platelets alter during asthmatic reactions induced by allergens, we studied nine subjects previously shown to develop an early or dual asthmatic reaction after inhalation challenge with extracts of house dust mite or grass pollen. In each subject, FEV1, circulating platelets and leucocytes were measured before, 15, 30 and 60 min, and 2, 4, 6 and 8 hr after inhalation of allergen and diluent control administered in a single-blind, randomized fashion. The same procedure was repeated in six of the nine subjects after bronchoconstriction induced by methacholine. Each subject developed an early asthmatic reaction after allergen inhalation challenge, which was followed by a late asthmatic reaction in six subjects and by an equivocal late asthmatic reaction in two of them (fall in FEV1 of 15 and 17% respectively). Compared with the control day, circulating platelets significantly decreased during the allergen-induced early asthmatic reaction (P less than 0.025, at 30 min). Platelet counts returned to baseline values within 4 hr and remained steady thereafter both in subjects who did and did not develop a late asthmatic reaction. No changes in platelet counts occurred after bronchoconstriction induced by methacholine. Diurnal increase of leucocyte numbers occurred after challenge with both allergen and diluent control. These results suggest that platelets may be involved in the pathogenesis of allergen-induced asthmatic reactions.

Furosemide prevents early and late allergen-induced asthmatic reactions

Furosemide prevents early and late allergen-induced asthmatic reactions

The beta-adrenergic system and allergic bronchial asthma: changes in lymphocyte beta-adrenergic receptor number and adenylate cyclase activity after an allergen-induced asthmatic attack

Beta-adrenergic receptor characteristics and adenylate cyclase responses to different stimuli were measured in lymphocyte membrane preparations of six normal control subjects and five allergic asthmatic patients with mild airways disease and increased bronchial reactivity to histamine and acetylcholine. The determinations were performed just before and 24 hr after inhalation challenge with house-dust mite antigen to investigate the influence of an allergen-induced asthmatic attack on the beta-adrenergic receptor system. Before the house-dust mite challenge, the lymphocyte membranes of the patients showed a normal receptor density, dissociation constant for (−) 3H-dihydroalprenolol, and adenylate cyclase response to isoproterenol, guanyl-5′-yl-imidodiphosphate, (GppNHp) and NaF. After the allergen-induced asthmatic reaction, however, the beta-adrenergic receptor number in the patients was significantly reduced by 21%, while the basal adenylate cyclase activity and isoproterenol-, GppNHp-, and NaF-induced cyclic AMP responses were simultaneously reduced by about 40%. The allergen challenge had no significant effect on the lymphocyte membranes of the control subjects. These results suggest (1) that a reduced beta-adrenergic function is not an intrinsic component of allergic bronchial asthma but is rather the consequence of an active disease state, and (2) that next to changes in beta-adrenergic receptor number, alterations distal to the receptor may play an important role in the observed decrease in beta-adrenergic responsiveness.

Levels of complement factors in human serum during immediate and late asthmatic reactions and during acute hypersensitivity pneumonitis.

In 16 asthmatic patients and in four subjects suspected of having hypersensitivity pneumonitis, serum levels of CH50, C3, C4, C5 and factor B were measured before, between 10 and 20 min, between 5 and 7 h and, in the latter group, also 24 h after allergen challenges provoking type I bronchial reactions or acute hypersensitivity pneumonitis. There was a significant decrease in one of the complement factors in two patients during the immediate asthmatic phase, but in no patient during the late asthmatic phase and in no patient with hypersensitivity pneumonitis. On the other hand, significant increases of C3, C4, and/or CH50 were seen in five patients during immediate asthmatic reactions, in seven patients during late asthmatic reactions and in all cases with hypersensitivity pneumonitis. However, with respect to the particular complement factors the vast majority of the patients showed no appreciable change. Investigations of C3 split products, which were done in seven patients gave negative results. No correlations existed between the changes in the levels of complement factors to increases of Raw, decreases of DLCO, size of skin test reactions or RAST scores. The cause and pathophysiological role of the non-uniform behaviour of serum complement levels after inhalation challenges is not yet clear; obviously both consumption and formation of complement factors take place during allergen-induced asthmatic reactions and hypersensitivity pneumonitis.