Bronchial hyperresponsiveness and airway wall remodelling induced by exposure to allergen for 9 weeks

Abstract

Prolonged exposure to allergen has been proposed to be important for the development of bronchial hyperresponsiveness and airway remodelling in asthma. The present study was designed to examine the effect of chronic allergen exposure on bronchial responsiveness, eosinophil infiltration, and airway remodelling. We sensitized brown Norway rats with the occupational allergen trimellitic anhydride (TMA) and exposed the animals to TMA conjugated to rat serum albumin (TMA-RSA) on 5 consecutive days each week for 9 weeks, starting 4 weeks after sensitization. IgE and IgG anti-TMA antibodies in serum and bronchial responsiveness to acetylcholine were evaluated before and at weeks 3, 6, and 9 of allergen exposure. Thickness of the airway wall, airway luminal narrowing, and the number of goblet cells and eosinophils in the airway wall were evaluated with an image analysis system in lungs resected after the last assessment of bronchial responsiveness, at the end of the 9-week allergen exposure. All rats developed IgE and IgG anti-TMA antibodies after sensitization. The levels of antibodies increased with allergen exposure until week 6, and then declined. Bronchial hyperresponsiveness to acetylcholine was induced in allergen-exposed rats without ongoing airway eosinophilia. Bronchial hyperresponsiveness induced by chronic allergen exposure via inhalation was accompanied by significantly increased thickness of smooth muscle and airway narrowing in the small airways, and goblet cell hyperplasia in the large airways. We conclude that chronic exposure to allergen can induce bronchial hyperresponsiveness and airway wall remodelling. Airway wall remodelling may contribute to bronchial hyperresponsiveness.

Dissociation between airway responsiveness to methacholine and responsiveness to antigen

“…In asthma, thickening of airway smooth muscles may lead to narrowing of the airways [19], and thus contribute to nonspecific AHR. This mechanism was postulated to be true in previous experiments, which used BN rats treated in a way similar to the present experiment [4,5]. Contrary to the present authors9 expectation, however, the morphological changes of the airways observed after 1 month of antigen challenges disappeared after 3-month repeated antigen challenges; and there were no significant differences in the morphology of the airways between the repeatedly antigen-challenged rats and the control rats.…”

“…In the same strain of rats, multiple antigen challenges are reported by some investigators to develop chronic abnormalities resembling those in asthma, such as airway remodelling [4,5]. In addition, it has been demonstrated that nonspecific AHR occurs after multiple antigen challenges in some reports [4][5][6][7][8]. In contrast, there have been a number of studies, which observed the generation of IgE isotype-specific tolerance [9,10] after multiple antigen challenges and also the attenuation of antigen-specific AHR.…”

“…These include production of an antigen-specific immunoglobulin-E (IgE) antibody [1], upregulation of T-helper 2 cytokines such as interleukin (IL)-4 and/or IL-5 [2], early and late phase airway reactions to the inhaled antigen [1], eosinophilic airway inflammation, and nonspecific airway hyperresponsiveness (AHR) to methacholine [3]. In the same strain of rats, multiple antigen challenges are reported by some investigators to develop chronic abnormalities resembling those in asthma, such as airway remodelling [4,5]. In addition, it has been demonstrated that nonspecific AHR occurs after multiple antigen challenges in some reports [4][5][6][7][8].…”

Chronic Exposure to Innocuous Antigen in Sensitized Mice Leads to Suppressed Airway Eosinophilia That Is Reversed by Granulocyte Macrophage Colony-Stimulating Factor

“…In sharp contrast, other studies have documented persistent airway eosinophilia (10,11). With respect to Igs, it has been shown in one study that prolonged exposure leads to persistent IgE production (11), while in another, prolonged exposure leads to transient IgG and IgE expression (9). While these discrepancies may reflect differences in the experimental models, our observations demonstrate that, in the mouse, chronic exposure to Ag does not a Mice were exposed to OVA in the context of GM-CSF for 2 or 4 wk.…”

“…This understanding is further limited by the fact that research examining the effect of chronic allergen exposure on airway inflammation has produced controversial results. Studies showing that chronic allergen exposure does not lead to persistence of airway inflammation (8,9) suggest that allergen alone is insufficient in perpetuating the inflammatory response. Others have documented persistent airway eosinophilia (10,11); however, the focus of these studies was on airway remodeling and lung physiology rather than on immune inflammatory processes.…”