A new house dust mite-driven and mast cell-activated model of asthma in the guinea pig

Abstract

Background: Animal models are extensively used to study underlying mechanisms in asthma. Guinea pigs share anatomical, pharmacological and physiological features with human airways and may enable the development of a pre-clinical in vivo model that closely resembles asthma.

Objectives: To develop an asthma model in guinea pigs using the allergen house dust mite (HDM).

Methods: Guinea pigs were intranasally sensitized to HDM which was followed by HDM challenges once weekly for five weeks. Antigen-induced bronchoconstriction (AIB) was evaluated as alterations in R_n (Newtonian resistance), G (tissue damping) and H (tissue elastance) at the first challenge with forced oscillation technique (FOT), and changes in respiratory pattern upon each HDM challenge were assessed as enhanced pause (Penh) using whole-body plethysmography. Airway responsiveness to methacholine was measured one day after the last challenge by FOT. Inflammatory cells and cytokines were quantified in bronchoalveolar lavage fluid, and HDM-specific immunoglobulins were measured in serum by ELISA. Airway pathology was evaluated by conventional histology.

Results: The first HDM challenge after the sensitization generated a marked increase in R_n and G, which was abolished by pharmacological inhibition of histamine, leukotrienes and prostanoids. Repeated weekly challenges of HDM caused increase of Penh and a marked increase in airway hyperresponsiveness for all three lung parameters (R_n , G and H) and eosinophilia. Levels of IgE, IgG₁ , IgG₂ and IL-13 were elevated in HDM-treated guinea pigs. HDM exposure induced infiltration of inflammatory cells into the airways with a pronounced increase of mast cells. Subepithelial collagen deposition, airway wall thickness and goblet cell hyperplasia were induced by repeated HDM challenge.

Conclusion and clinical relevance: Repeated intranasal HDM administration induces mast cell activation and hyperplasia together with an asthma-like pathophysiology in guinea pigs. This model may be suitable for mechanistic investigations of asthma, including evaluation of the role of mast cells.