Airways hyperresponsiveness and the effects of lung inflation

Lung inflation has a beneficial effect on the airways of healthy subjects. It acts as a bronchoprotector, that is to prevent bronchoconstriction, and as a bronchodilator, in that it reverses bronchial obstruction. The bronchoprotective effect of deep inspiration is more potent than the bronchodilatory one, and the two phenomena appear to advocate different mechanisms. Asthmatics and rhinitics with airways hyperresponsiveness show an impairment in bronchoprotection induced by deep breaths, whereas the bronchodilatory effect, although reduced, is still effective. The lack of the bronchoprotective effect of deep inspiration may contribute to the development of airways hyperresponsiveness. The mechanisms through which lung inflation exerts its beneficial role in healthy subjects, and the factors impairing such an effect in those with airways hyperresponsiveness, are currently under investigation.     

Inflammatory mediators in late antigen-induced rhinitis

To investigate the mechanisms responsible for the late-phase response in patients with allergies, we measured four biochemical mediators (histamine, tosyl-L-arginine methyl ester [TAME]-esterase, kinin, and prostaglandin D2) in nasal secretions after nasal challenge with pollen antigen in 12 patients with allergy. Nine patients had an immediate response and a recurrence of symptoms 3 to 11 hours after challenge. The clinical symptoms during recurrence were accompanied by a second increase in levels of histamine, TAME--esterase, and kinin over base-line values, although kinin levels were lower than during the immediate response. In contrast, although the levels of prostaglandin D2 were significantly increased during the immediate response, they did not increase above base line during the late response. Rechallenge with allergen 11 hours after the initial provocation, however, was associated with reappearance of all four biochemical mediators, including prostaglandin D2. We conclude that the late response to nasal challenge with allergen is accompanied by a second increase in the concentrations of histamine and TAME--esterase but differs from the immediate response in the lack of prostaglandin D2 production and in the amount of kinin generated. Since histamine is released only by mast cells and basophils and prostaglandin D2 is not produced by basophils, we suggest that these cells are partly responsible for the late-phase response.     

The effects of the nasal antihistamines olopatadine and azelastine in nasal allergen provocation.

BACKGROUND: Olopatadine, an antihistamine used in allergic conjunctivitis, is under development as a nasal preparation for the treatment of allergic rhinitis. OBJECTIVES: To evaluate the efficacy of olopatadine in suppressing symptoms and biomarkers of the immediate reaction induced by nasal allergen provocation and to compare olopatadine with azelastine in the same model. METHODS: The study was approved by the Johns Hopkins University institutional review board, and all subjects gave written consent. We studied 20 asymptomatic subjects with seasonal allergic rhinitis. The study had 2 randomized, double-blind, placebo-controlled, crossover phases that evaluated 2 concentrations of olopatadine, 0.1% and 0.2%. In a third exploratory phase, olopatadine, 0.1%, was compared with topical azelastine, 0.1%, in a patient-masked design. Efficacy variables were the allergen-induced sneezes, other clinical symptoms, and the levels of histamine, tryptase, albumin, lysozyme, and cysteinyl-leukotrienes (third study only) in nasal lavage fluids. RESULTS: Both concentrations of olopatadine produced significant inhibition of all nasal symptoms, compared with placebo. Olopatadine, 0.1%, inhibited lysozyme levels, but olopatadine, 0.2%, inhibited histamine, albumin, and lysozyme. The effects of olopatadine, 0.1%, were comparable to those of azelastine, 0.1%. CONCLUSIONS: Olopatadine, at 0.1% and 0.2% concentrations, was effective in suppressing allergen-induced nasal symptoms. At 0.2%, olopatadine provided evidence suggestive of inhibition of mast cell degranulation.     

Absence of nasal mucosal atrophy with fluticasone aqueous nasal spray

OBJECTIVE: To evaluate whether 1 year of continuous treatment with intranasal fluticasone propionate would lead to atrophy in the nasal mucosa compared with an active control, oral terfenadine. DESIGN: Prospective, randomized, multicenter, open-label, parallel-group study. SETTING: Two tertiary care academic institutions. PATIENTS: Seventy-five subjects older than 18 years with perennial allergic rhinitis. INTERVENTIONS: Patients received either fluticasone propionate aqueous nasal spray, 200 microg once daily, or terfenadine, 60 mg twice daily, for 1 year. Nasal biopsy specimens were obtained before and after 1 year of treatment and were evaluated for evidence of atrophy. MAIN OUTCOME MEASURES: Epithelial and collagen layer thickness of the nasal mucosa as assessed by light microscopy and the presence and degree of edema, and regularity of collagen fibrils as assessed by electron microscopy. Analyses were performed without knowledge of subject identity or treatment assignment. RESULTS: Neither fluticasone nor terfenadine treatment led to atrophy in the nasal mucosa by clinical or histologic observation. No significant changes from baseline were observed for any assessment of atrophy. In contrast to what would have been expected if atrophy were to occur, mean epithelial layer thickness in the fluticasone group significantly increased compared with terfenadine treatment (P = .03). CONCLUSIONS: Treatment with intranasal fluticasone for 1 year increases the thickness of the nasal epithelium as compared with a year's treatment with terfenadine and does not lead to atrophy in the nasal mucosa. The increased thickness in the fluticasone treatment may represent repair from epithelial damage caused by chronic allergic inflammation.     

Demonstration of inhibition of mediator release from human mast cells by azatadine base. In vivo and in vitro evaluation

In vitro experimentation using dispersed human lung mast cells demonstrated that azatadine base, a compound with known H1-antihistamine properties, inhibited anti-IgE-induced release of histamine and leukotriene C4 by 45% and 85%, respectively. To assess the clinical relevance of these findings and to compare in vitro mast cell data with results obtained in vivo, nasally instilled azatadine was tested in a double-blind, placebo-controlled clinical trial in which nasal challenges with antigen were performed on eight allergic individuals. Pretreatment with azatadine significantly suppressed the number of sneezes following antigen challenge and inhibited the associated elevations in histamine, kinins, and enzyme(s) hydrolyzing the artificial substrate N-alpha-tosyl-L-arginine-methyl-ester in nasal secretions, whereas placebo was inactive. Hence, we showed agreement between our in vitro and in vivo experimental models of the allergic reaction. Topical application of azatadine base has the potential to become an effective antiallergic treatment.     

Influx of kininogens into nasal secretions after antigen challenge of allergic individuals.

We have recently demonstrated that kinins are generated in vivo after nasal challenge with antigen of allergic, but not nonallergic, individuals. The present study was undertaken as a first step in determining the mechanism(s) of kinin formation during the allergic reaction and was directed towards establishing the availability and origin of kininogens in nasal secretions. Allergic individuals (n = 6) and nonallergic controls (n = 5) were challenged with antigen; and by using specific radioimmunoassays, nasal washes, obtained before and after challenge, were assayed for high molecular weight kininogen (HMWK), total kininogen (TK), albumin, and kinins. Dramatic increases in HMWK (1,730 +/- 510 ng/ml), TK (3,810 +/- 1035 ng/ml), kinin (9.46 +/- 1.75 ng/ml), and albumin (0.85 +/- 0.2 mg/ml) were observed after challenge of allergic individuals which correlated (P less than 0.001) with increases in histamine and N-alpha-tosyl-L-arginine methyl esterase activity and with the onset of clinical symptoms. For nonallergic individuals, levels of kininogens, albumin, and all mediators after antigen challenge were not different from base line. Linear regression analysis revealed excellent correlations (P less than 0.001 in each case) between increases in HMWK, TK, kinin, and albumin during antigen titration experiments and between the time courses of appearance and disappearance of HMWK, TK, kinin, and albumin after antigen challenge. Gel filtration revealed no evidence of degradation products of kininogens in nasal washes. For each allergic individual the ratio of HMWK/TK in postchallenge nasal washes was similar to the ratio of these two proteins in the same individual's plasma. These data suggest that, during the allergic reaction, there is an increase in vascular permeability and a transudation of kininogens from plasma into nasal secretions, where they can provide substrate for kinin-forming enzymes.     

Deep inspiration-induced changes in lung volume decrease with severity of asthma

We have previously reported that the magnitude of deep inspiration (DI)-induced bronchodilation is only slightly reduced in mild asthmatics, compared to healthy subjects. The aim of this study was to evaluate whether increased severity of asthma is associated with impairment in the ability of DI to induce changes in lung volume. Thirty-six consecutive asthmatics recruited from the Pulmonary and the Allergy Outpatient Clinics of the Institute of Respiratory Diseases of the University of Palermo were divided into 3 groups: Intermittent (I), Mild Persistent (MP) and Moderate-Severe (MS), based on GINA guidelines. Single dose methacholine (Mch) bronchoprovocations were performed in the absence of DI, to induce at least 15% reduction in inspiratory vital capacity (IVC) from baseline. The post-Mch IVC was followed by 4 consecutive DI and by another IVC, to determine the bronchodilatory effect of DI. The bronchodilatory effect of DI was found to significantly decrease with increasing severity of asthma (I: 68+/-5.4%, MP: 45+/-7.2%, MS: 4+/-15.6%; ANOVA: P<0.0001). Bronchodilation by DI, but not FEV(1) or FEV(1)/FVC, was also inversely correlated to symptom scores (r=-0.42, P=0.01) and to weekly salbutamol usage (r=-0.47, P=0.004). These observations provide support to the hypothesis that the attenuation of the bronchodilatory effect of DI contributes to the severity of the clinical manifestations of asthma.