Subjects with mild and moderate asthma respond to segmental allergen challenge with similar, reproducible, allergen-specific inflammation.

BACKGROUND: The relationship between severity of asthma and bronchial inflammation is poorly understood. OBJECTIVE: We examined acute and subacute inflammatory responses to allergen in subjects with mild and moderate persistent asthma to evaluate whether different cellular and mediator responses to endobronchial allergen challenge are associated with differences in disease severity. METHODS: Segmental allergen challenge was performed in 8 subjects with mild and 10 subjects with moderate allergic asthma to compare baseline airways inflammation and allergen-induced inflammatory responses 24 hours later. This evaluation was repeated after 6 weeks in 9 subjects to investigate the reproducibility of these inflammatory responses. RESULTS: Subjects with mild and moderate asthma had similar decreases in FEV(1) in response to segmental allergen challenge (9.1% +/- 4.2% vs 15.1% +/- 4.6%, P = .35). There was no difference in inflammatory cell counts or cytokine concentrations in the groups with mild and moderate asthma at baseline or after saline or allergen challenge. Repeat segmental allergen challenge 6 weeks later showed that these cellular and cytokine responses were reproducible. CONCLUSION: Segmental allergen challenge in subjects with mild and moderate asthma produces similar allergen-specific physiologic and inflammatory responses that are reproducible 6 weeks later. In this model of allergic asthma, acute responses to allergen do not appear to be related to disease severity.

Anti-inflammatory effects of zileuton in a subpopulation of allergic asthmatics.

The objective of this study was to determine the effects of allergen exposure on leukotriene generation and inflammation within the airways of allergic asthmatics and evaluate the effects of the 5-lipoxygenase inhibitor zileuton on these responses. We measured leukotriene-B(4) (LTB(4)) and LTC(4)/D(4)/E(4), inflammatory cytokine mediators, and cellular responses in bronchoalveolar lavage fluid (BALF) before and 24 h after segmental ragweed antigen challenge in 18 asthmatic subjects at baseline. Before initiating therapy with the 5-lipoxygenase inhibitor or placebo, only nine of 18 asthmatic subjects had a significant increase (234 +/- 102-fold, mean +/- SE) in BALF LTC(4)/D(4)/E(4) levels 24 h after segmental antigen challenge, whereas leukotriene levels were essentially unchanged (1.14 +/- 0.22-fold) in the other nine subjects. The high LT producers also had higher postantigen BALF levels of LTB(4), total protein, IL-5, IL-6, TNF-alpha, and recovery of more eosinophils than the low LT producers. Treatment with the 5-lipoxygenase inhibitor zileuton reduced postantigen BALF eosinophil count by 68% in the high LT producers, but had no detectable effect on BALF composition in the low LT producers. These data suggest that leukotriene inhibition may be more effective in a subset of asthmatics in whom leukotrienes are a major contributory factor in causing allergic inflammation.

T-Cell repertoire in the blood and lungs of atopic asthmatics before and after ragweed challenge.

T cells play a pivotal role in initiating and orchestrating allergic responses in asthma. The goal of this work was to learn whether ragweed challenge in the lungs alters the T-cell repertoire expressed in the blood and lungs of atopic asthmatics. Analyses of cell numbers, differentials, and T-cell subsets in bronchoalveolar lavage (BAL) fluids showed that ragweed challenge was associated with preferential recruitment of CD4+ T cells into the lungs. A reverse transcriptase-polymerase chain reaction (RT-PCR) was used to amplify T-cell receptor (TCR) gene transcripts from unfractionated, CD4+, and CD8+ T cells in blood and BAL fluids. As judged by RT-PCR, the usage of TCR Valpha and Vbeta gene families in BAL fluids was similar to that in blood. Ragweed challenge did not change the levels of expression of these V gene families. The clonality of T cells was estimated by analyzing the diversity of TCR V-(D)-J junctional region nucleotide lengths associated with each Valpha and Vbeta gene family, using sequencing gel electrophoresis. Most V gene families in blood and BAL fluids were associated with multiple junctional region lengths before and after ragweed challenge, indicating polyclonal expression. Some V gene families were expressed in an oligoclonal manner in unfractionated, CD4+, and CD8+ T cells in BAL fluids before ragweed challenge, as indicated by a few predominant junctional region lengths. The majority of these V gene families became polyclonal after challenge, compatible with polyclonal T-cell influx during inflammation immediately after ragweed challenge. However, some V gene families became oligoclonal or developed a new oligoclonal pattern of junctional region lengths in BAL T cells after ragweed challenge. Surprisingly, this occurred in both CD4+ and CD8+ T cells. In one of these instances, DNA sequencing of Vbeta21 junctional regions in CD8+ T cells confirmed a change from polyclonal to oligoclonal expression after ragweed challenge. These findings show that ragweed challenge is associated with polyclonal influx and oligoclonal activation of both CD4+ and CD8+ T cells in the lungs.

Inhibition of exercise-induced bronchospasm by zileuton: a 5-lipoxygenase inhibitor.

Recent evidence suggests that leukotrienes may have a causative role in exercise-induced asthma. Twenty-four subjects with exercise-induced asthma received either 600 mg zileuton, a 5-lipoxygenase inhibitor, or a placebo four times daily for 2 d prior to exercise challenge (a total of nine doses). The last dose was administered in the laboratory 2 h before the exercise challenge. There was no bronchodilation after nine doses of the 5-lipoxygenase inhibitor (p=0.95). The administration of zileuton inhibited bronchospasm after exercise challenge by 40.75% as compared with placebo. Five minutes after the completion of exercise, the zileuton group's FEV1 was 85.76% of the preexercise value, compared with 73.92% of the preexercise value in the placebo group (p<0.01). The maximum percent change in baseline FEV1 after zileuton was a 15.58% decrement from the preexercise level, as compared with a 28.1% decrease after placebo (p<0.001). Five minutes after exercise, the FVC after zileuton was 92.76% of the preexercise value, as compared with 86.26% after placebo (p<0.05). This is the first study in which a 5-lipoxygenase inhibitor has been shown to attenuate exercise-induced asthma. These results suggest that leukotrienes are important biochemical mediators in the development of exercise-induced bronchospasm, and that leukotriene inhibit may have a role in the treatment of this disorder.

Dysregulation of airway cytokine expression in chronic obstructive pulmonary disease and asthma.

Cigarette smoking is the major factor responsible for chronic obstructive pulmonary disease (COPD). COPD occurs in a minority of smokers, but the host factors that modify risk of disease have not been clearly elucidated. There is significant clinical and histopathologic overlap between COPD and asthma, including the accumulation and activation of airway inflammatory cells. These two disorders are compared and contrasted. Abnormal airway inflammatory cytokine expression in these disorders is discussed.