4.9.7 Respiratory Disease Models
Respiratory disease models are used to evaluate candidate bronchodilator, anti-inflammatory, and disease-modifying agents for asthma and chronic obstructive...
Respiratory disease models are used to evaluate candidate bronchodilator, anti-inflammatory, and disease-modifying agents for asthma and chronic obstructive pulmonary disease, two of the most prevalent chronic respiratory conditions worldwide.
Asthma — Ovalbumin-Induced Allergic Airway Inflammation Model
Allergic asthma is modelled by sensitising mice or guinea pigs to the model allergen ovalbumin, administered by intraperitoneal injection together with an adjuvant (commonly aluminium hydroxide) to promote a Th2-skewed immune response, followed by repeated ovalbumin aerosol or intranasal challenge to elicit allergic airway inflammation localised to the lung. The resulting phenotype closely mirrors human allergic asthma, including airway eosinophilia, elevated serum and bronchoalveolar lavage IgE and Th2 cytokines (IL-4, IL-5, IL-13), goblet cell hyperplasia with mucus hypersecretion, and, critically, airway hyperresponsiveness to a bronchoconstrictor challenge (commonly methacholine), measured by whole-body or invasive plethysmography. Standard reference comparators include inhaled corticosteroids (such as dexamethasone) and, increasingly, biologic agents targeting the Th2 pathway (such as anti-IL-5 or anti-IgE antibodies), reflecting the evolving clinical management of allergic asthma. This model's principal strength is its comprehensive recapitulation of the allergic (Th2-driven) asthma endotype; it is less representative of non-allergic or neutrophilic asthma phenotypes, which are modelled using alternative sensitisation protocols.
Chronic Obstructive Pulmonary Disease (COPD) — Cigarette Smoke-Induced Model
Chronic obstructive pulmonary disease, characterised by progressive, largely irreversible airflow limitation resulting from chronic bronchitis and emphysema, is modelled by chronic whole-body or nose-only exposure of mice or rats to cigarette smoke, generated by a controlled smoking machine, for extended periods (commonly several hours daily, five days per week, for eight to twenty-four weeks depending on the severity of pathology desired). This exposure protocol reproduces the oxidative stress, chronic airway and parenchymal inflammation (neutrophil- and macrophage-predominant, distinguishing it from the eosinophilic asthma model), and progressive alveolar destruction (emphysema) characteristic of human COPD. Endpoints include bronchoalveolar lavage inflammatory cell counts and cytokine profiling, lung function measurement (compliance and airway resistance by whole-body plethysmography), and histopathological quantification of alveolar airspace enlargement (mean linear intercept). Long-acting bronchodilators (beta-2 agonists and muscarinic antagonists) and inhaled corticosteroids serve as standard reference comparators, though the relatively modest efficacy of these agents in slowing human COPD progression is itself reflected in the model's continued use for identifying genuinely disease-modifying, rather than purely symptomatic, therapeutic candidates.