Plasma histamine and bronchial reactivity in allergic asthma

Histamine is an important mediator of allergic inflammation and bronchial hyperresponsiveness (BHR), a hallmark of asthma. Studies on the relationship between plasma histamine and BHR in allergic asthmatic patients have yielded controversial results. We therefore measured plasma histamine and bronchial reactivity in 30 nonsmoker volunteers taking no medication. Eleven were normal subjects; 19 were stable, mildly allergic asthmatic patients. Venous blood was taken to measure blood cells and basal plasma histamine by radioimmunoassay. After blood sampling, all subjects underwent a measurement of PC₂₀M (concentration of methacholine causing a 20% fall in FEV₁). Mean plasma histamine levels were 0.21 ± 0.1 ng/ml and 0.44 ± 0.3 ng/ml in normal and asthmatic subjects, respectively (P<0.05). We found a significant increase of blood eosinophils and basophils in asthmatic patients, and a positive correlation between plasma histamine and circulating basophils. PC₂₀M was greater than 16 mg in normal volunteers, and mean PC₂₀M was 2.1 ± 2 mg/ml in asthmatic patients. PC₂₀M did not correlate with plasma histamine levels, but it did so negatively with blood eosinophils. The increased plasma histamine concentration in mildly atopic asthmatic patients might be a consequence of the high basophil releasability of atopies and the higher basophil counts in allergic asthma. Plasma histamine is thus unlikely to be a determinant of BHR in asthma.     

Effect of ethanol on airway caliber and nonspecific bronchial responsiveness in patients with alcohol-induced asthma

No study has investigated the effects of ethanol on bronchial responsiveness in patients with alcohol-induced asthma, although acetaldehyde, which is a metabolite of ethanol and is thought to be a main factor in alcohol-induced asthma, causes both bronchoconstriction and bronchial hyperresponsiveness. The purpose of this study was to investigate the direct action of ethanol on the airway in patients with alcohol-induced asthma. First, we investigated the bronchial response to inhalation of ascending doses (5, 10, and 20%) of ethanol in nine patients with alcohol-induced asthma. Then, the bronchial responsiveness to methacholine was measured in 14 patients who were pretreated with saline or 20% ethanol in a double-blind, randomized, placebo-controlled, crossover fashion. Ascending doses of inhaled ethanol caused no significant changes in FEV₁. The methacholine concentrations producing a 20% fall in FEV₁ (PC₂₀-MCh) after 20% ethanol (0.769 mg/ml, GSEM 1.514) were significantly ( P = 0.0357) higher than those after saline (0.493 mg/ml, GSEM 1.368). This indicates that ethanol has a reducing effect on nonspecific bronchial responsiveness in patients with alcohol-induced asthma; this paper is the first report on the effects of ethanol on bronchial responsiveness.     

Comparison of four different measures of bronchial responsiveness in asthmatic children

Although several tests are available to assess the presence and severity of bronchial hyperresponsiveness (BHR), there is no agreement on the most appropriate stimulus. The most commonly used stimuli are methacholine, histamine, and exercise. Daily peak expiratory flow (PEF) variation has been reported to correlate with the severity of BHR, and in recent years this has been widely used because of its noninvasiveness and ease of performance. This study was carried out to determine the relationship among these four commonly used measures of bronchial responsiveness in asthmatic children. For this purpose, 12 asthmatic children of varying disease severity were recruited. Subjects underwent three challenges on 3 separate days in 1 week. During the week preceding the challenges (methacholine, histamine, and exercise), patients recorded PEF three times a day. All patients had PC₂₀ less than 8 mg/ml with methacholine and histamine. Patients with PC₂₀ greater than 3.5 mg/ml for both methacholine or histamine had negative exercise challenges. The strongest correlation was between histamine and methacholine ( r =0.95). Exercise-induced bronchospasm had substantial and significant correlation with the other three measures. No significant correlation was observed between PEF variability and histamine or methacholine. The varying degrees of relationships among the four commonly used measures suggests that each method yields information on different but related phenomena. More than one measure may be required to detect the different aspects of asthmatic bronchial responsiveness.     

Blood markers of early and late airway responses to allergen in asthmatic subjects. Relationship with functional findings

We evaluated the relationship between blood markers of mast-cell (plasma histamine and serum level of heat-stable neutrophil chemotactic activity [NCA]) and eosinophil (serum eosinophil cationic protein [ECP]) activation during early airway response (EAR) and late airway response (LAR) to allergen inhalation in 24 asthmatic subjects. After EAR, 14 subjects showed significant LAR (FEV₁ fall: 25%), while 10 subjects showed equivocal LAR (FEV₁ fall: 15–20%). A significant increase from baseline value was observed in plasma histamine and in serum NCA during both EAR and LAR, while serum ECP significantly increased only during LAR. The sensitivity of different markers to detect significant FEV₁ fall during EAR and LAR was low, except for NCA. Changes in blood mediators were similar in both groups with significant and equivocal LAR. There was a significant relationship between the increase in NCA during EAR and the severity of LAR. Stepwise regression between changes in different blood markers showed a significant relationship between histamine increase during EAR and ECP increase during LAR. Thus, serum NCA is a more sensitive marker of EAR and LAR than plasma histamine and serum ECP, and its increase during EAR seems predictive of the severity of the subsequent LAR.     

The Protective Property of Equipotent Bronchodilating Doses of Inhaled KWD 2131 and Terbutaline against Allergen-Induced Bronchospasm

The anti-allergic capacity of nebulized KWD 2131 in inhibiting allergen-induced bronchospasm was compared with that of terbutaline in equipotent bronchodilating doses. It was a double-blind cross-over and randomized study also including placebo. Twelve symptom-free extrinsic asthmatics participated in the trial. Equipotent bronchodilating doses of the two β-receptor-agonists were established in a histamine challenge procedure before the start of the study. Allergen challenge was performed with double concentration steps every 10 min until a ≥20% decrease in FEV₁ was achieved. Significanty (P<0.001) more allergen dose steps could be used after pretreatment with KWD 2131 and terbutaline than with placebo. No difference could be observed between the active compounds. The same allergen log dose gave a 20% decrease in FEV₁ after pretreatment with KWD 2131 and terbutaline. The active compounds' protective properties did not differ at a lower degree of allergen challenge. The plasma histamine level was not significantly changed at any point of allergen challenge after pretreatment with either placebo or the active compounds. Therefore, plasma histamine determination was of no value for evaluating the inhibition of mediator release by these drugs. It is concluded that the anti-allergic property of KWD 2131 at allergen challenge does not give any further clinical value besides the brochodilating property.     

Sputum eosinophil counts and eosinophil cationic protein levels in cough-variant asthma and in classic asthma, and their relationships to airway hypersensitivity or maximal airway response to methacholine

Background:  The aims of this study were to compare the degree of airway inflammation in cough-variant asthma (CVA) with that in classic asthma (CA), and to examine the relationship between airway inflammation and airway hypersensitivity or maximal airway response to methacholine in both conditions.
Methods:  Sputum was induced in 41 CVA patients, in 41 methacholine PC₂₀-matched CA patients, and in 20 healthy children. The sputum samples were analyzed for total and differential cell counts, and for eosinophilic cationic protein (ECP). A high-dose methacholine challenge test was performed in CVA and CA patients to determine PC₂₀ and maximal airway response.
Results:  Sputum eosinophil percentages and ECP levels were significantly elevated in CVA and CA vs the control, but no significant differences were found between the two asthma groups. In the two asthma groups, neither sputum parameters correlated significantly with methacholine PC₂₀. However, the absence of a maximal response plateau or its higher level, when present, was associated with increased eosinophil percentages and ECP levels in the CVA group.
Conclusions:  The degree of eosinophilic inflammation may not be causally related to differences in presented asthma manifestations. The identification of a maximal response plateau and the level of this plateau in patients with CVA may provide information pertinent to airway eosinophilic inflammation.     

Studies on histamine metabolism in allergen-induced asthma

The excretion of histamine (Hi) and its metabolite methythistamine (MeHi)was determined in separated fractions of urine up to 12h alter standardized allergen provocations in 18 adult patients wild defined extrinsic bronchial asthma. The main histamine metabolite, methylimidazoleacetic acid (MelmAA), was measured in six of the patients.
After positive provocations (decrease in FEV₁ > 20%) the excretion of Hi was significantly increased during 3h and that of MeHi during 4h after challenge. Negative provocations (decrease in FEV₁ <20%) were not followed by any changes in the excretion of Hi and MeHi. MelmAA excretion increased in five out of six patients after positive provocation. It was calculated that the increased excretion of Hi and its metabolites after a positive provocation corresponded to a release of about 1 mg histamine in the body or about 1 μg/g lung tissue if all histamine was liberated in the lung.
Pretreatment with two anti-allergic drugs, disodium cromoglycate and ICI 74.917, giving significant allergen protection, resulted in a smaller increase of the excretion of both Hi and MeHi, indicating an inhibition of histamine release in vivo.     

Double-blind trial of house-dust mite immunotherapy in asthmatic children resident at high altitude

Twenty-three Dermatophagoides pteronyssinus (Dpt)-sensitive asthmatic children aged 7–14 years entered a double-blind, placebo-controlled trial of standardized immunotherapy (IT) (Alpare) while resident at high altitude. Dpt sensitivity was evaluated by skin prick tests at different allergen concentrations at the enrollment and after 6 and 12 months of treatment. Bronchial hyperreactivity was evaluated at the same time points, and on each occasion, histamine challenge and, the following day, Dpt bronchial challenge were performed. All patients, irrespective of active treatment, improved clinically and in lung function with increased PC₂₀ and Dpt-PD₂₀. Alpare-treated patients had a significantly decreased sensitivity on Dpt skin testing (P ≤0.009) and felt that their asthma had improved (P ≤0.001) compared with placebo-treated subjects, but there was no difference between the treatment groups in lung function or bronchial challenge response. IT neither increased nor decreased bronchial histamine sensitivity. Our results indicate that Dpt IT benefits asthmatic children, but improvement by allergen avoidance at high altitude is even greater.     

Recovery of FEV1 after histamine challenge in asthmatic children

Factors that influence the time necessary for complete recovery of FEV₁ after inhaling histamine were analysed in forty-five children with asthma. These included the initial bronchial obstruction (baseline FEV₁), the provocation dose of histamine producing a 20% fall in FEV₁ (PD₂₀) and the fall in FEV₁ after the histamine challenge. In addition it was also investigated whether a second challenge carried out after complete recovery of FEV₁ would produce a reproducible PD₂₀-histamine value. The time for complete recovery varied widely from 15 to more than 75 min. The time needed for complete recovery of FEV₁ after the histamine challenge seems to be mainly determined by the PD₂₀ value. The other factors such as initial bronchial obstruction and the fall in FEV₁ after the challenge showed no significant relationship with the recovery time. A second challenge with histamine resulted in a highly reproducible PD₂₀ value. The clinical implication of this study is that other tests can only be performed when FEV₁ has returned to 95% of baseline.     

Inhaled lysine acetylsalicylate (L-ASA) attenuates histamine-induced bronchoconstriction in asthma

When administered by inhalation, histamine provokes dose-related bronchoconstriction in asthmatic subjects mainly by a direct activation of histamine H1-receptors on airway smooth muscle. However, little is known of the change in airway responsiveness to histamine after cyclooxygenase blockade. The aim of the study was to investigate the effect of the potent cyclooxygenase inhibitor, lysine acetylsalicylate (L-ASA), administered by inhalation on histamine-induced bronchoconstriction in a group of 16 asthmatic subjects. The subjects studied attended the laboratory on four separate occasions to receive nebulized L-ASA (solution of 90 mg/ml) or matched placebo (glycine solution of 30 mg/ml) 15 min before bronchoprovocation tests with histamine and methacholine in a randomized, double-blind order. Changes in airway caliber were followed as forced expiratory volume in 1 s (FEV₁), and agonist responsiveness was expressed as the provocative concentration causing a 20% fall in FEV₁ from baseline (PC₂₀). Administration of both L-ASA and glycine solution caused a small but significant acute fall in FEV₁ from baseline, which returned to normal within 15 min. When compared to placebo, inhaled L-ASA reduced the airway responsiveness to histamine in 13 of the 16 subjects studied, the geometric mean (range) values for PC₂₀ histamine increasing significantly ( P < 0.001) from 1.72 (0.13–5.49) mg/ml to 3.31 (0.36–12.00) mg/ml after placebo and L-ASA, respectively. No significant change in airway responsiveness to methacholine was recorded after L-ASA. Acute administration of L-ASA by inhalation protects the asthmatic airways against histamine-induced bronchoconstriction, thus suggesting that endogenous prostaglandins may play a contributory role in the airways response to histamine in human asthma.     

Role of tachykinin NK1 and NK2 receptors in allergen-induced early and late asthmatic reactions, airway hyperresponsiveness, and airway inflammation in conscious, unrestrained guinea pigs

Using a guinea pig model of allergic asthma, we investigated the effects of the inhaled, highly selective nonpeptide tachykinin NK₁ and NK₂ receptor antagonists SR 140333 and SR 48968, respectively, on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions, and infiltration of inflammatory cells in the airways. Both SR 140333 (100 nM, 3 min) and SR 48968 (100 nM, 3 min) had no effect on the severity of the EAR, while the NK₂ receptor antagonist SR 48968, but not the NK₁ receptor antagonist SR 140333, caused significant inhibition of the LAR. SR 140333 significantly reduced the allergen-induced AHR to histamine, both after the EAR and the LAR. By contrast, SR 48968 did not affect the AHR after the EAR, but significantly attenuated the AHR after the LAR. Bronchoalveolar lavage studies performed after the LAR indicated that SR 140333 caused significant inhibition of allergen-induced infiltration of eosinophils, neutrophils and lymphocytes, while SR 48968 attenuated the infiltration of neutrophils and lymphocytes, but not of eosinophils. Both NK receptor antagonists tended to reduce the accumulation of ciliated epithelial cells in the airways. These results indicate that NK₁ and NK₂ receptors are importantly, but differentially, involved in the development of allergen-induced airways obstruction, AHR and infiltration of inflammatory cells in the airways. Therefore, both NK₁ and NK₂ receptor antagonists, or dual NK₁ and NK₂ antagonists, could be useful in the treatment of allergic asthma.     

Comparison of the effects on bronchial hyperresponsiveness of antiallergic agents and beclomethasone dipropionate in long-term bronchial asthma

The effect of antiallergic agents (DSCG (disodium cromoglycate), ketotifen, and ibudilast) and beclomethasone dipropionate inhaler (BDI) on bronchial hyperresponsiveness to histamine inhalation was retrospectively assessed in 72 asthmatic patients with more than a year's duration of the disease. Decrease in bronchial hyperresponsiveness to histamine was observed in 10 out of the 33 (30%) antiallergic-agents-treated patients (group A, mean duration = 7.8 months), in 12 of 19 (63.2%) BDI-treated patients (group B, 6.2 months), but only 2 of the 20 (10%) control patients (group C, 7.8 months). Improvement of histamine PC₂₀ was from 310 to 597 μg/ml ( P <0.01) in group A, from 308 to 1622 μg/ml ( P <0.0005) in group B, and from 575 to 525 μg/ml (NS) in group C. A significant decrease in the peripheral eosinophil count was observed only in group B. The improvement in bronchial hyperresponsiveness was parallel with that of asthmatic symptoms; the percentage of patients becoming symptom-free rose from 12 to 42%, 5 to 89%, and 5 to 20% in groups A, B, and C, respectively. Out of 11 unimproved patients in group A, 7 showed a significant improvement in their histamine PC₂₀ by BDI treatment (mean PC₂₀: 311 → 1828 μg/ml). These results suggest that BDI might be more effective than antiallergic agents in the treatment of patients with long-standing bronchial asthma.     

Validated safety predictions of airway responses to house dust mite in asthma

BACKGROUND: House dust mite (HDM) is the most common aeroallergen causing sensitization in many Western countries and is often used in allergen inhalation challenges. The concentration of inhaled allergen causing an early asthmatic reaction [provocative concentration of inhaled allergen causing a 20% fall of forced expiratory volume in 1 s (FEV(1))(PC(20) allergen)] needs to be predicted for safety reasons to estimate accurately the severity of allergen-induced airway responsiveness. This can be accomplished by using the degree of non-specific airway responsiveness and skin sensitivity to allergen. OBJECTIVE: We derived prediction equations for HDM challenges using PC(20) histamine or PC(20) methacholine and skin sensitivity data obtained from patients with mild to moderate persistent asthma and validated these equations in an independent asthma population. METHODS: PC(20) histamine or PC(20) methacholine, skin sensitivity, and PC(20) allergen were collected retrospectively from 159 asthmatic patients participating in allergen challenge trials. Both the histamine and methacholine groups (n=75 and n=84, respectively), were divided randomly into a reference group to derive new equations to predict PC(20) allergen, and a validation group to test the new equations. RESULTS: Multiple linear regression analysis revealed that PC(20) allergen could be predicted either from PC(20) methacholine only ((10)log PC(20) allergen=-0.902+0.741.(10)log PC(20) methacholine) or from PC(20) histamine and skin sensitivity (SS) ((10)log PC(20) allergen=-0.494+0.231.(10)log SS+0.546.(10)log PC(20) histamine). In the validation study, these new equations accurately predicted PC(20) allergen following inhalation of HDM allergen allowing a safe starting concentration of allergen of three doubling concentrations below predicted PC(20) allergen in all cases. CONCLUSION: The early asthmatic response to inhaled HDM extract is predominantly determined by non-specific airway responsiveness to methacholine or histamine, whereas the influence of the cutaneous sensitivity to HDM appears to be rather limited. Our new equations accurately predict PC(20) allergen and hence are suitable for implementation in HDM inhalation studies.     

Endogenous interleukin-10 suppresses allergen-induced airway inflammation and nonspecific airway responsiveness

BACKGROUND: The airway inflammation observed in asthma is orchestrated by activated Th-2 lymphocytes relevant for the induction of altered airway responsiveness. An increasing body of evidence is accumulating that not only the pro-inflammatory cytokines interleukin (IL)-4 and IL-5 but also the immunomodulating cytokines IL-12 and possibly IL-10 are crucial for regulating the allergic airway inflammation. OBJECTIVE: Since IL-10 is capable of downregulating a broad spectrum of pro-inflammatory cytokines, we wanted to address the role of endogenously produced IL-10 in vivo in allergic asthma. METHODS: Knockout (IL-10(-/-)) mice (C57BL/6-IL10tm1Cgn) and wild-type (WT) counterparts were immunized (day 0) and exposed (day 14-21) to ovalbumin (OVA). Airway inflammation and reactivity (AR), serum allergen-specific IgE responses and cytokine profiles in the bronchoalveolar lavage fluid (BALF) were studied. RESULTS: The IL-10(-/-) mice had more eosinophilic airway inflammation but comparable levels of allergen-specific serum IgE compared to the WT mice after allergen challenge. The AR was comparably increased in the OVA challenged WT and IL-10(-/-) mice vs sham-exposed WT, but not vs sham-exposed IL-10(-/-)mice since these showed a higher baseline AR. IFN gamma, IL-4 and IL-13 were comparable and IL-5 was even lower in the BALF of the in IL-10(-/-) mice compared to the similarly exposed WT mice. CONCLUSION: These results indicate that IL-10 plays an important and possibly direct role in the control of airway inflammation and responsiveness in an in vivo mouse model of allergy.     

Appearance of allergen-induced increases in airway responsiveness only after repeated allergen inhalations in two subjects

Observations in two subjects undergoing three allergen challenges for a drug study suggested 'priming' of the late sequelae, namely allergen-induced increase in airway responsiveness. Both subjects had rhinitis and asthma limited to the ragweed season, near normal out-of-season histamine PC20, and extreme IgE sensitivity to ragweed. Both had an isolated early response with no change in histamine PC20 after the first allergen challenge. Significant (3.5- to 5.8-fold) reductions in histamine PC20 occurred after the second and third allergen challenge in Subject 1, and after the third challenge in Subject 2; this was associated with equivocal 5-8% late responses. Such a 'priming' effect, the prevalence of which is not known, may be important in the pathogenesis of naturally occurring allergic asthma, and in the design of clinical trials involving repeated allergen inhalations.     

Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma

Background:  Pitrakinra is a recombinant protein derived from human interleukin-4 (IL-4) that binds to IL-4Rα and acts as a competitive antagonist of IL-4 and IL-13. The studies reported here compare the dose-ranging effects of pitrakinra on allergen-induced airway hyperresponsiveness (AHR) and airway eosinophilia when administered subcutaneously (s.c.) or by inhalation to the Ascaris suum -sensitive cynomolgus monkey for the purpose of elucidating the primary site of pitrakinra's anti-asthmatic action.
Methods:  Airway responsiveness to inhaled methacholine and bronchoalveolar lavage cell composition was determined before and after three allergen exposures with a 1-week course of twice-daily (b.i.d.) s.c. or inhaled pitrakinra or placebo treatment.
Results:  Treatment with s.c. pitrakinra significantly reduced allergen-induced AHR, with a maximum effect of a 2.8- to 3.8-fold increase in methacholine PC₁₀₀ relative to control ( P  < 0.05) observed at b.i.d. s.c. doses of 0.05–0.5 mg/kg. Inhaled pitrakinra also significantly reduced AHR with a similar maximum effect of a 2.8- to 3.2-fold increase in methacholine PC₁₀₀ relative to control ( P  < 0.05) at nominal b.i.d. doses of 3–100 mg. The maximal effect on AHR following inhalation was observed at a plasma concentration which exhibited no efficacy via the subcutaneous route. The effect of pitrakinra on lung eosinophilia was not statistically significant following either route of administration, although lung eosinophil count was reduced in all studies relative to control.
Conclusion:  Local administration of pitrakinra to the lung is sufficient to inhibit AHR, one of the cardinal features of asthma, indicating the therapeutic potential of inhaled pitrakinra in the treatment of atopic asthma.     

Inhibitory effect of levocabastine on allergen-induced increase of nasal reactivity to histamine and cell influx

For evaluation of the effect of levocabastine pretreatment on allergen-induced rhinitis symptoms, changes in nasal washings, and nasal responsiveness to histamine, 12 asymptomatic patients with documented allergic rhinitis participated in a single-blind, placebo-controlled study. Eight-day treatment with levocabastine (twice in each nostril, four times a day) caused significant reduction in nasal symptoms and inflammatory cell influx after allergen challenge, as compared with placebo administration. Levocabastine inhibited increased nasal reactivity to histamine induced by allergen provocation, as controlled by rhinitis symptoms and albumin level in nasal washings. These data reveal a high effectiveness of levocabastine in the prevention of allergen-induced rhinitis symptoms. Moreover, its inhibitory effect on inflammatory cell influx and hyperresponsiveness to histamine suggest that levocabastine is more than a simple H₁-receptor antagonist.     

Predictors of early- and late-phase reactions to bronchial allergen challenge

The influence of inhaled steroids and predictive factors on the response to bronchial allergen challenge (BCA) was evaluated in. 80 asthmatics allergic to Dermatophagoides pteronyssinus (Der p). All underwent BCA with Der p and measurement of early (EAR) and late asthmatic reaction (LAR). The cumulative dose of allergen producing 20% fall in FEV₁, in the EAR (PD₂₀) was calculated. Bronchial histamine provocation, conjunctival provocation test (CPT), and skin prick test with Der p extract were performed. Specific IgE to Der p in serum (RAST), blood eosinophil (EOS) count, serum eosinophil cationic protein, and eosinophil protein X were measured. Thirty patients (38%) were treated with inhaled steroids. All patients had at least a 20% fall in FEV₁ in EAR. Some 42% of nonsteroid- and 33% of steroid-treated patients had LAR with fall in peak flow of at least 20%. For patients not treated with steroid, 35% of variation in PD₂₀ was explained by RAST and histamine reactivity, and 53% of variation of observed PD₂₀ could be predicted. The baseline FEV₁, EOS, and EAR explained 28% of variation in LAR, and 28% of variation in observed LAR could be predicted. For patients treated with steroids, 38% of variation in PD₂₀ was explained by EOS and histamine reactivity, and only 18% of variation of observed PD₂₀ could be predicted. For patients treated with steroids, it was impossible to predict LAR. We conclude that to achieve a quantitative estimation of allergen-specific EAR and LAR, BCA cannot be replaced by the tests used in this study. Treatment with inhaled steroids modifies the response to BCA, making quantitative prediction of EAR less accurate and prediction of the magnitude of LAR impossible.     

Changes in airway responsiveness and β- and α-adrenergic receptors in the lungs of guinea pigs with experimental asthma

The effects of inhaled allergen on airway responsiveness and on beta- and alpha-1-adrenergic receptors on lung membrane were investigated in guinea pigs. After measuring the respiratory threshold to histamine (RT-HIS), one group of guinea pigs passively sensitized for ovalbumin was challenged by allergen inhalation (challenged group). Measurement of the RT-HIS 24 h following challenge revealed a significant decrease from 687 micrograms/ml (mean, n = 16) to 407 micrograms/ml (P less than 0.05). In addition the RT-HIS 24 h after challenge was also significantly lower in the challenged group than in controls (n = 9, P less than 0.05). The density of beta-adrenergic receptors on the lung membrane of the challenged group was 594 +/- 32 (mean +/- SE) fmol/mg protein (n = 11) compared with 712 +/- 24 fmol/mg protein (n = 9) in the controls, a statistically significant difference (P less than 0.05). A significant correlation was found between the RT-HIS and density of beta-adrenergic receptors. From these results, we concluded that the exaggerated airway responsiveness 24 h after allergen challenge is in part due to a decrease in the density of beta-adrenergic receptors. There was no difference in the density of alpha-1-adrenergic receptors nor a significant correlation between the RT-HIS and the number of alpha-1-adrenergic receptors in the challenged vs. the control groups.     

Ozone inhalation induces exacerbation of eosinophilic airway inflammation and hyperresponsiveness in allergen-sensitized mice

Background:  Ozone (O₃) exposure evokes asthma exacerbations by mechanisms that are poorly understood. We used a murine model to characterize the effects of O₃ on allergic airway inflammation and hyperresponsiveness and to identify factors that might contribute to the O₃-induced exacerbation of asthma.
Methods:  BALB/c mice were sensitized and challenged with Aspergillus fumigatus ( Af ). A group of sensitized and challenged mice was exposed to 3.0 ppm of O₃ for 2 h and studied 12 h later (96 h after Af challenge). Naive mice and mice exposed to O₃ alone were used as controls. Bronchoalveolar lavage (BAL) cellular and cytokine content, lung function [enhanced pause (P_enh)], isometric force generation by tracheal rings and gene and protein expression of Fas and FasL were assessed. Apoptosis of eosinophils was quantified by FACS.
Results:  In sensitized mice allergen challenge induced a significant increase of P_enh and contractile force in tracheal rings that peaked 24 h after challenge and resolved by 96 h. O₃ inhalation induced an exacerbation of airway hyperresponsiveness accompanied by recurrence of neutrophils and enhancement of eosinophils 96 h after allergen challenge. The combination of allergen and O₃ exposure inhibited Fas and FasL gene and protein expression and eosinophil apoptosis and increased interleukin-5 (IL-5), granulocyte-macrophage-colony stimulating factor (GM-CSF) and G-CSF protein levels.
Conclusions:  O₃ affects airway responsiveness of allergen-primed airways indirectly by increasing viability of eosinophils and eosinophil-mediated pathological changes.