Nitric oxide regulation of asthmatic airway inflammation with segmental allergen challenge,☆☆

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Abstract

Background: Despite evidence of increased nitric oxide (NO) in asthmatic compared with healthy individuals, the role of NO in airway inflammation is unclear. Objective: The purpose of the study was to determine the in vivo effects of localized allergen challenge on airway NO levels and transcription factor activation. Methods: In this study localized allergen challenge was used as a model of asthmatic exacerbation to determine the relationship of NO to airway inflammation. Results: With allergen challenge, asthmatic patients had a rise in airway NO levels, whereas NO levels in healthy controls did not change. The increased NO in asthma with allergen challenge compared with healthy control subjects was associated with an increase in inflammatory cytokines (GM-CSF and macrophage inflammatory protein-1) in epithelial lining fluid and eosinophilic infiltrate in bronchoalveolar lavage fluid (BAL) and biopsy specimens. To investigate the mechanisms of cytokine gene expression, activation of the transcription factors activator protein-1 and nuclear factor-κB (NF-κB) in cells from BAL were evaluated. Activator protein-1 was not activated before or after local allergen challenge. In contrast, NF-κB activation was less in BAL cells from asthmatic patients with increased NO in comparison with controls. Conclusion: Our studies are the first to suggest an inverse correlation between NF-κB and airway NO in a localized segmental allergen challenge model in allergic asthmatic patients. The current study demonstrates that activation of the inflammatory response (eg, cytokines, cellular infiltrate) in allergic asthmatic patients is temporally associated with increased airway NO. We propose that NO that is up-regulated by cytokines is part of an autoregulatory feedback loop (ie, allergen challenge stimulates inflammatory cytokine production, which in turn stimulates NO production, and NO down-regulates cytokine production). (J Allergy Clin Immunol 1999;104:1174-82.)

Section snippets

Subjects

Six healthy control subjects and 8 patients with mild asthma were recruited for the study at the Cleveland Clinic (Table I).

. Characteristics of study population

Patient No.Age (y)SexBaseline FEV1 (L)Baseline FEV1 (% predicted)13A-PD20 by WLAC (PNU/mL)Maximum Ag by WLAC (PNU/mL)Fall in FEV1 at maximumAg (%)Ag for SACSAC dose (PNU in 10 mL of NS)
Asthmatic
129F2.89881,0001,000–20Grass100
244F2.58982,4553,162–21Grass300
340F3.05100232316–28Grass30
438F2.7497250316–25Grass100
531F3.37961,4413,162–40Grass

Inflammatory cells

At baseline the BALs from the healthy control subjects and the asthmatic patients were not different in total cell recovery, viability, or cellular differential (Table II). The allergen-challenged segment from the asthmatic group had a significant increase in the percent of eosinophils at 48 hours (P = .02, t test) and a corresponding decrease in the percent of macrophages. However, the absolute number of macrophages was slightly increased (Table II). Fig 1 shows the increase in eosinophils

DISCUSSION

The relationship between NO and asthma has not been conclusively defined. Airway NO levels in asthmatic patients are heterogeneous, with some patients in the same range as healthy control subjects. Whether this variation in airway NO levels corresponds to disease activity is not known. All the patients in the current study had mild asthma. Allergen-induced late asthmatic reactions have been associated with increased exhaled NO.20 Glucocorticoids decrease exhaled NO.5 Beneficial effects of

Acknowledgements

We thank Rita Piccin for recruiting and patient scheduling, Daniel Laskowski for assistance with airway NO measurements, Marusia Oleksiuk for allergen preparation, and Marc Lewis and Suzy Comhair for performing the urea assays.

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    Reprint requests: Mary Jane Thomassen, PhD, Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Desk A90, 9500 Euclid Ave, Cleveland, OH 44195-5038.

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