Asthma: the feline connection.
Explore the source record for details and available documents.
Allergens↗
Biomedical subjects
W J Metzger
Publications and source records attributed to W J Metzger.
Adenosine-induced bronchoconstriction and contraction of airway smooth muscle from allergic rabbits with late-phase airway obstruction: evidence for an inducible adenosine A1 receptor.
Recently, there has been an increasing interest in adenosine as a potential mediator of allergic asthma. In the present study, we used the allergic rabbit model developed in our laboratory to study the airway responses to adenosine and receptor binding in allergic lung vs. normal. Neonatal, pathogen-free rabbit litter mates were injected intraperitoneally within 24 hr of birth with ragweed pollen extract (1 mg/ml) to produce preferentially allergen-specific immunoglobulin E. Immunization produced bronchial airway hyperresponsiveness. Aerosolized adenosine (0.156-10 mg/ml) caused a dose-dependent bronchoconstriction (PC50 adenosine = 1.64 +/- 0.84 mg/ml). 9-Chloro-2-(2-furyl)[1,2,4]triazole[1,5- c]quinazolin-5-amine (CGS-15943), a nonxanthine adenosine receptor antagonist, significantly inhibited the adenosine-induced airway obstruction in term of dynamic compliance (P < .05). Adenosine also increased the lung resistance in a dose-dependent manner which was significantly inhibited by CGS-15943 (P < .05). Nonimmunized, pathogen-free, age-matched rabbits (control) did not respond to adenosine at these same concentrations. Adenosine also produced a concentration-dependent (10(-9)-10(-4) M) contraction of isolated tracheal and bronchial airway rings in vitro from allergic rabbits but had no detectable effect on normal rabbit airway smooth muscle. Peripheral airway smooth muscles (secondary and tertiary) were more responsive to adenosine than central (tracheal) airways. The contraction produced by 10(-4) M adenosine in primary, secondary and tertiary airways was 90, 135 and 265% of the contraction produced by 50 mM KCl, respectively. CGS-15943 (10(-7) M) significantly inhibited the adenosine-induced contraction (P < .05) shifting the dose-response curve to the right.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine↗
Intranasal flunisolide spray as an adjunct to oral antibiotic therapy for sinusitis.
BACKGROUND: The diagnosis of sinusitis is difficult and there are few controlled studies of customary therapies. In particular, the possible role of topical intranasal steroid as an adjunct to antibiotic treatment has not been evaluated. METHODS: The study was a multicenter, double-blind, randomized, parallel trial in which patients aged 14 years or older were recruited from allergy practices. All patients had maxillary sinusitis documented by radiographs. Treatment consisted of amoxicillin/clavulanate potassium 500 mg combined with nasal spray of either 100 micrograms flunisolide or placebo to each nostril three times a day for 3 weeks (phase I) followed by administration of flunisolide or placebo nasal spray alone three times a day for 4 weeks (phase II). RESULTS: Clinical symptoms and signs decreased significantly in both treatment groups during phase I (p < 0.01). There was a trend to greater improvement in the patients treated with flunisolide, but only the decrease in turbinate swelling/obstruction was statistically significant at the end of phase I when compared with placebo (p = 0.041). Patients' global assessment of overall effectiveness of treatment was higher for flunisolide than placebo after phase I (p = 0.007) and after phase II (p = 0.08). Maxillary sinus radiographs showed improvement in both treatment groups during phase I (p < 0.004) with somewhat greater regression of abnormal findings in patients treated with flunisolide after phase II (p = 0.066). However, 80% of radiographs were still abnormal at the end of phase I. All types of inflammatory cells were significantly decreased in nasal cytograms in patients treated with flunisolide in comparison with those treated with placebo. Flare-up of sinusitis during phase II occurred in 26% of with those treated with placebo. Flare-up of sinusitis during phase II occurred in 26% of patients treated with flunisolide and 35% of those treated with placebo and tended to be more severe in the latter, although these differences were not statistically significant. Adverse events, mainly gastrointestinal symptoms and headache, were similar in both groups and more frequent in phase I than in phase II, (42 vs 15 patients); these side effects were probably due to the antibiotic. CONCLUSION: The addition of flunisolide topical nasal spray as an adjunct to antibiotic therapy was most effective in global evaluations, tended to improve symptoms, to decrease inflammatory cells in nasal cytograms, to normalize ultrasound scans, and to aid regression of radiographic abnormalities compared with placebo spray.
Administration, Inhalation↗
Adenosine-induced bronchoconstriction in an allergic rabbit model: antagonism by theophylline aerosol.
Recently, there has been an increasing interest in the involvement of adenosine as a mediator of allergic asthma. In the present study, we have employed an allergic rabbit model to study the airway responses to adenosine. The rabbit litter mates were injected i.p., within 24 h of birth, with ragweed pollen extract to preferentially produce ragweed-specific IgE. This allergic rabbit model demonstrates many clinical features of asthma similar to human allergic asthma. Aerosolized adenosine (0.156-10 mg/ml) caused a concentration-dependent bronchoconstriction. The normal rabbits (non-immunized) did not respond to adenosine within that concentration range. Theophylline significantly inhibited the adenosine-induced bronchoconstriction. These early studies suggest that adenosine differentiated asthmatic airways from normal airways and adenosine-induced bronchoconstriction in this model was mediated through specific cell surface receptor(s).
Adenosine↗
Modification of allergen-induced airway obstruction and bronchial hyperresponsiveness in the allergic rabbit by theophylline aerosol.
The effects of theophylline on allergen-induced airway obstruction and bronchial hyperresponsiveness were investigated in allergic rabbits. This allergic rabbit model was developed in our laboratory and stimulates the human model of allergic asthma in several aspects. Four allergic rabbits with hyperreactive airways were challenged with ragweed to elicit early- and late-phase asthmatic responses and subsequent increased airway responsiveness. Two to three weeks later, the rabbits received theophylline (5 mg/ml, nebulized for 3 min) prior to a second allergen challenge. Theophylline significantly inhibited the allergen-induced early- and late-phase asthmatic responses by 38% (P < 0.05) and 49% (P < 0.05), respectively. Further theophylline inhibited the allergen-induced increase in lung resistance by 42% (P < 0.05) during the late-phase responses. Theophylline also inhibited the allergen-induced bronchial hyperresponsiveness by 39% (P < 0.05) at 24 h. These data suggest a potential anti-inflammatory effect of theophylline in preventing allergen-induced asthmatic responses and bronchial hyperresponsiveness.
Aerosols↗
Bronchial challenge with adenosine causes the release of serum neutrophil chemotactic factor in asthma.
In order to investigate the mechanism of adenosine-induced bronchoconstriction in asthma, serum neutrophil chemotactic activity (NCA) was measured in normal individuals and patients with asthma before and 5 min after bronchoprovocation testing with adenosine. Challenge testing was terminated when the FEV1 fell by 20% or a concentration of 10 mg/ml was reached. Participants were separated into three groups: six asthmatics hyperresponsive to adenosine (Group 1), seven asthmatics hyperresponsive to histamine but not adenosine (Group 2), and six normal subjects (Group 3). The mean percentage increase in NCA was 84% for Group 1 (p less than 0.001), 29% for Group 2 (p less than 0.05), and only 13% for Group 3. No significant increase in NCA was observed after histamine challenge in seven individuals with asthma derived from Groups 1 and 2. Four patients from Group 1 were rechallenged after treatment with therapeutic doses of oral theophylline. Theophylline therapy was associated with a significant attenuation of the increase in NCA at the concentration of adenosine which caused a 20% decrease in FEV1 before treatment (18% versus 84%, p less than 0.01). The concentration of adenosine which caused a 20% drop in FEV1 was increased at least twofold for each of the four patients. Analysis of NCA by gel filtration chromatography demonstrated an increase in a high molecular weight neutrophil chemotactic factor in the serum of two Group 1 patients after adenosine challenge. Release of a high molecular weight neutrophil chemotactic factor is consistent with a mast cell source for inflammatory mediators in adenosine-induced bronchoconstriction. The therapeutic effects of theophylline, a potent adenosine antagonist, in asthma may therefore occur in part through the inhibition of this process.
Adenosine↗
Recurrent allergic vulvovaginitis: treatment with Candida albicans allergen immunotherapy.
Recurrent vaginal candidiasis is a difficult problem for many women who do not respond to the usual antifungal agents. Normally these women have recurrent disease for many years before they are referred for evaluation of local vaginal hypersensitivity. We evaluated 18 women with recurrent vulvovaginal candidiasis that was unresponsive to all other modalities of therapy and who were skin-test positive to Candida albicans with a positive prick test or intradermal skin test. Three patients had late-phase skin test reactions only. Of the 18 study participants, 16 responded with significant improvement in the mean incidence of episodes of vaginitis per year from 17.2 +/- 2.0 to 4.3 +/- 1.8 (p less than 0.0004). Overall, there was approximately 79% improvement in these patients. More than half the women were also atopic but were not first seen with these allergic symptoms. These data suggest that certain women who have chronic vaginal candidiasis may have a local hypersensitivity response to Candida that may improve with allergy immunotherapy with C. albicans extract. A double-blind, placebo-controlled trial in a homogeneous group of women with standardized extract is needed to establish this as a recommended form of therapy in this subgroup of patients.
Adult↗
Clinical role of bronchoalveolar lavage in adults with pulmonary disease.
BAL remains a powerful investigative tool. In a short span of 20 yr, it has helped tremendously in understanding some of the aspects of the pathogenesis of diseases involving the lower respiratory tract. To realize its full potential in the diagnosis and management of diseases involving the lower respiratory tract, there is a great need for standardization of the technical aspects of BAL as well as processing and analysis of the BAL cellular- and fluid-phase components. Despite these hurdles, BAL has been found to be diagnostic in several infectious and noninfectious diseases involving the lower respiratory tract, and it provides valuable information that may be helpful in characterizing the prognosis and response to therapy in certain interstitial diseases of the lung. It is expected that with future research, in particular long-term prospective epidemiologic and clinical studies in pneumoconioses and in other interstitial lung disease, BAL will prove more valuable in the diagnosis and management of such disease.
Bronchoalveolar Lavage Fluid↗
The requirement for platelets in allergen-induced late asthmatic airway obstruction. Eosinophil infiltration and heightened airway responsiveness in allergic rabbits.
In these studies, we have used an allergic rabbit model to investigate the role of platelets in the late asthmatic response (LAR) by depleting platelets with a guinea pig antirabbit platelet antiserum (APAS). Allergen exposure of immunized rabbits pretreated with normal guinea pig serum (NGPS) to serve as a control resulted in an early- and late-phase obstructive airway response that persisted for 6 h. When the immunized animals were pretreated with APAS, the magnitude of the LAR in terms of dynamic compliance was reduced by 86.2% (p less than 0.03), but there was no difference in the early response curve. Allergen challenge of animals treated with NGPS resulted in an increased bronchial responsiveness to inhaled histamine: PD50 Cdyn geometric mean +/- SEM before, 2.36 mg/ml (3.43-1.64); after, 0.60 mg/ml (0.67-0.54) (p less than 0.01). PD50 RL before, 1.78 mg/ml (2.4-1.32); after, 0.58 mg/ml (0.81-0.47) (p less than 0.05). In contrast, when animals were treated with APAS, there was a significant inhibition of allergen-induced airway hyperresponsiveness to inhaled histamine: PD50 Cdyn geometric mean +/- SEM before, 1.42 mg/ml (2.06-0.98); after, 1.10 mg/ml (1.41-0.86) (p less than 0.4). PD50 RL before, 1.62 mg/ml (2.22-1.39); after, 1.05 mg/ml (1.35-0.82) (p greater than 0.4). Analysis of bronchoalveolar lavage fluid revealed an increase in the number of neutrophils and eosinophils after allergen exposure in control animals (p less than 0.01). However, in animals rendered thrombocytopenic, the number of eosinophils, but not neutrophils, was significantly reduced (p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
Allergens↗
Evaluation of symptom relief, nasal airflow, nasal cytology, and acceptability of two formulations of flunisolide nasal spray in patients with perennial allergic rhinitis.
A new formulation of intranasal flunisolide containing less propylene glycol was compared with the original formulation for efficacy and acceptability in more than 200 patients with symptoms of perennial allergic rhinitis. In this multicenter, randomized, double-blind, parallel group study, symptomatic patients were treated with either the new or the original formulation of 0.025% solution of intranasal flunisolide for 4 weeks to provide 200 micrograms flunisolide daily. Both formulations were highly effective in decreasing symptom scores as evident from patient diary reports before and after treatment (P less than .001). Similarly, nasal airflow was improved with each treatment as measured by anterior rhinomanometry (P less than .0002) and the number of patients with nasal eosinophilia decreased (P less than .01). Finally, fewer patients using the new formulation reported nasal burning or stinging and the acceptability rating of the new formulation was higher.
Administration, Topical↗
Indications for allergen immunotherapy during pregnancy.
Allergen immunotherapy has been proven to be an efficacious and valuable tool in the treatment of the allergic patient with perennial rhinitis who is intolerant of medications or has moderate to severe asthma. It may also be useful for the allergic pregnant patient to reduce the severity of asthma or rhinitis, and possibly to prevent the complications of severe asthma. It may reduce the use of other medications that are undesirable during pregnancy. Allergen immunotherapy has been shown to be safe for both the mother and fetus during pregnancy. It does not need to be stopped during pregnancy, but the maintenance dose should be modified. Immunotherapy plays an important role in the treatment of severe allergic disease by virtue of its capacity to reduce airway hyperresponsiveness and late-phase airway responses that lead to inflammation and chronic symptoms.
Asthma↗
Modification of allergen-induced airway obstruction and airway hyperresponsiveness in an allergic rabbit model by the selective platelet-activating factor antagonist, BN 52021.
Allergen challenge of eight ragweed-immunized rabbits elicited a prolonged airway obstruction that was evident during the 6-hour study period. Airway responsiveness to histamine was enhanced 24 hours after allergen exposure (geometric mean of the 50% reduction in effective dose [ED50] of dynamic compliance [Cdyn] before challenge, 3.46 mg/ml, decreased to 0.52 mg/ml after challenge, p less than 0.01; pulmonary resistance ED50 geometric mean before challenge, 3.50 mg/ml, decreased to 0.65 mg/ml after challenge, p less than 0.05). In a random crossover study, the selective platelet-activating factor antagonist, BN 52021 (60 mg/kg, orally, 1 hour before allergen challenge), significantly reduced the allergen-induced airway obstruction (p less than 0.005). In addition, pretreatment with BN 52021 reduced the associated increased airway responsiveness induced by allergen exposure (prechallenge Cdyn ED50, 1.93; after challenge, 2.13 mg/ml; pulmonary resistance ED50, 1.91 mg/ml before challenge and 1.69 mg/ml after challenge). These present observations suggest a role for platelet-activating factor in the pathogenesis of allergen-induced airway obstruction and in the development of airway hyperresponsiveness in an allergic rabbit model.
Airway Obstruction↗
Platelets in bronchoalveolar lavage from asthmatic patients and allergic rabbits with allergen-induced late phase responses.
Explore the source record for details and available documents.
Animals↗
Increased bronchovascular permeability after allergen exposure in sensitive asthmatics.
To investigate the possibility that an increase in bronchovascular permeability is associated with allergen exposure in sensitive asthmatics we evaluated the amounts of serum proteins in bronchoalveolar lavage (BAL) effluents before and after local challenge with allergen. After exposure of sensitive asthmatic airways (n = 15) to allergen significant increases in total protein compared with controls were observed: 0.08 +/- 0.01 mg/ml in control airways and 0.13 +/- 0.02 mg/ml in challenged airways; P less than 0.05. The greatest changes induced by allergen exposure involved small-molecular-weight proteins (less than 345,000) and an inverse correlation was observed between log molecular weight and percent increase in the concentrations of the specific proteins; r = -0.61. BAL-serum distribution coefficients of serum proteins in airway fluids reflected a greater diffusability of low-molecular-weight proteins immediately after allergen exposure. We also evaluated the movement of serum proteins into lung after local allergen exposure using intravenously administered 99mTc-albumin (n = 10) and found an immediate 3.8-fold increase in amounts of radioactive albumin in allergen exposed airways compared with airways exposed to diluent. Most of the radioactivity was recovered in the first 5 ml of aliquot withdrawn, suggesting a marked increase in the permeability of the bronchial (large airway) vascular-epithelial membrane. An increase in serum proteins was also observed in BAL fluid of asthmatics 2-4 h after aerosol challenge (n = 4), including all proteins in the molecular weight range 45,000-900,000. These studies suggest that allergen exposure in sensitive asthmatics causes an acute increase in bronchovascular permeability to serum proteins.
Allergens↗
Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs. Description of the model and local airway inflammation.
The local mechanisms that result in the cellular inflammation and bronchial airway hyperreactivity that characterize allergic bronchial asthma are poorly defined. In order to study these processes, we developed a method for local allergen challenge using a fiberoptic bronchoscope and direct observation and bronchoalveolar lavage (BAL) to assess the airway responses to allergen. In these studies, 11 allergic asthmatics (all of whom had previously demonstrated a late-phase asthmatic response to aeroallergen challenge) and 6 healthy, asymptomatic subjects volunteered to undergo bronchoalveolar lavage after local airway challenge via a bronchoscope wedged into subsegmental airways. These studies revealed that asthmatic airways respond to allergen with an immediate pallor followed by reactive hyperemia, edema, and bronchial narrowing. This site and a control site were relavaged at 48 or 96 h after the immediate response. Neutrophils and eosinophils increased significantly at 48 h after challenge, as did helper T-lymphocytes. Characteristically, at 96 h, neutrophil counts returned to normal values, whereas eosinophiles and helper T-cells remained elevated. Peroxidase-staining cells were also elevated at 48 h after local allergen challenge. Electron microscopy revealed degranulation of mast cells and eosinophils, both immediately and later (48 and 96 h) after local allergen challenge. Macrophages were highly activated and had phagocytized, partially intact granules from both eosinophils and mast cells. There was a significant correlation (p less than 0.001) between the concentration of allergen required to produce a visible airway response and a positive end-point skin titration in the asthmatic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness.
Using a sensitive single isotope enzymatic assay we measured bronchoalveolar lavage (BAL) fluid histamine in asymptomatic normal (nonallergic), allergic rhinitic, and allergic asthmatic subjects. Normal subjects were found to have little or no detectable amounts of histamine in BAL fluid (11 +/- 11 pg/ml), and few BAL fluid mast cells. In comparison, the allergic rhinitics and allergic asthmatics had much higher amounts of BAL fluid histamine (113 +/- 53 and 188 +/- 42 pg/ml, respectively), and a significantly greater number of BAL fluid mast cells. Furthermore, despite having equivalent baseline pulmonary function values, allergic asthmatics with BAL fluid histamine levels greater than 100 pg/ml required only 7 +/- 2 breath units of methacholine to induce a 20% drop in forced expiratory volume in 1 s (FEV1) (PD20FEV1) while asthmatics with BAL fluid histamine levels less than 100 pg/ml required 49 +/- 19 breath units (P less than 0.05). These data suggest that allergic asthmatics have ongoing lung mast cell degranulation that might contribute to the etiology of airway hyperresponsiveness.
Adolescent↗
Generation and partial characterization of eosinophil chemotactic activity and neutrophil chemotactic activity during early and late-phase asthmatic response.
Asthma has been recognized to consist of hyperresponsive airways and cellular inflammation. Allergen bronchoprovocation (BPC) may define the early (EAR) and late-phase asthmatic response (LAR). The LAR has now been associated with increased nonspecific airway hyperresponsiveness and cellular inflammation consisting of neutrophils and eosinophils. We used BPC to demonstrate EAR and LAR in 12 subjects with seasonal allergic asthma. One normal subject and one subject with asthma who had been treated with allergy immunotherapy were challenged but did not respond. Plasma was sampled at frequent intervals during these aeroallergen challenges and assayed for eosinophil chemotactic activity (ECA) and neutrophil chemotactic activity (NCA). Of the 12 subjects with asthma who were challenged, nine had dual responses (both EAR and LAR), and three subjects demonstrated only an LAR. Those subjects who had dual airway responses had biphasic rises in both ECA (early = 267 +/- 28%; late = 286 +/- 28%) and NCA (early = 279 +/- 24%; late = 215 +/- 15%) in their plasma, whereas those subjects who demonstrated only an LAR had only a late rise in ECA (218 +/- 61%) and NCA (188 +/- 31%). The two individuals who did not respond to aeroallergen challenge demonstrated no change in their plasma chemotactic activity toward either eosinophils or neutrophils. Those individuals with the most severe LAR (greater than or equal to 1,000 mm2) had combined ECA plus NCA peak values of greater than 500%.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Bronchoalveolar lavage of allergic asthmatic patients following allergen bronchoprovocation.
In these studies, we describe the use of bronchoalveolar lavage (BAL) to study local changes following aerosol bronchoprovocation (BPC) and environmental exposure to antigen in mildly symptomatic asthmatic patients. The BAL was performed in 12 atopic subjects "out of season," and in five normal subjects at baseline, less than or equal to 4, or 24 hours following BPC. Five asthmatic patients were also lavaged during seasonal exposure to allergen. The BAL cells were examined with light and transmission electron microscopy. Bronchoprovocation, by itself, resulted in an average maximal decrease in FEV1 of 13 percent just prior to BAL. There was no significant decrease in FEV1 as a result of BAL. Within four hours after BPC, the number of neutrophils was significantly greater in BAL compared to baseline (1.5 +/- 0.6 X 10(5) vs 3.4 +/- 1.7 X 10(5) cells; p less than 0.01), and the number of eosinophils was significantly greater within four hours and at 24 hours when compared to baseline values (0.4 +/- 0.3 X 10(5) vs 1.9 +/- 0.7 X 10(5) vs 1.2 +/- 0.4 X 10(5) cells; p less than 0.02). Transmission electron micrographs of BAL from lungs of asthmatic patients revealed degranulation of mast cells and loss of core material from eosinophil granules following challenge with aerosolized allergen or with spontaneous environmental exposure. These studies show that in carefully selected, mildly symptomatic asthmatic subjects, BPC and BAL may be useful to evaluate pathogenetic mechanisms in allergic bronchial asthma.
Adolescent↗