Date of Graduation

1996

Document Type

Dissertation/Thesis

Abstract

Asthma is a chronic lung disease characterized by reversible airway obstruction and nonspecific airway hyperreactivity. Recent evidence suggests that inflammation is a critical feature in the pathogenesis of asthma. Central to the genesis of inflammation is the presentation of antigens to T lymphocytes. Dendritic cells (DC) are antigen presenting cells that activate T lymphocytes thought to play a critical role in stimulating antigen-induced airway inflammation and hyperreactivity in asthma. Even though the guinea pig is commonly used as an animal model of asthma, the role of pulmonary DC in the pathogenesis of asthma has not been investigated. Therefore, this study characterized the localization and prevalence of DC in guinea-pig airways, both in normal animals and in relation to airway inflammation and hyperreactivity in an asthma model. Subcutaneous ovalbumin (OVA) sensitization followed 3 weeks later by challenge with inhaled OVA aerosol until the onset of labored breathing was utilized as the model of asthma. Using a two-chamber whole body plethysmograph, basal specific airway resistance and breathing frequency of conscious animals were measured as indices of pulmonary obstruction at 1 min before OVA challenge, 1 min after challenge, and 18 hr post-challenge. Airway reactivity to inhaled methacholine (MCh) was assessed before and 18 hr after OVA exposure. The prevalence of DC and other inflammatory cells was assessed 18 hr post-OVA challenge in tracheal and bronchial sections through the use of quantitative immunohistochemistry techniques. Pharmacological modulation of OVA-induced responses by pre-treatment with aerosols of fluticasone propionate and pentamidine isethionate, two anti-inflammatory compounds, was also studied. Pulmonary obstruction was observed immediately after OVA challenge and was resolved by 18 hr. Airways became inflamed by 18 hr, and DC and eosinophils were elevated in the airways. No changes in macrophages, CD4{dollar}\\sp+{dollar} T lymphocytes, or B lymphocytes were observed. At 18 hr, guinea pigs became hyperreactive to inhaled MCh. After treatment with fluticasone or pentamidine, the increases in DC and eosinophils were inhibited and hyperreactivity to MCh was not observed. These results suggest that (i) antigen-induced airway inflammation and hyperreactivity are related events, and (ii) pulmonary DC are more prevalent during inflammation.

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