Oral tolerance attenuates airway inflammation and remodeling in a model of chronic pulmonary allergic inflammation

https://doi.org/10.1016/j.resp.2008.09.007Get rights and content

Abstract

We investigated the effects of oral tolerance (OT) in controlling inflammatory response, hyperresponsiveness and airway remodeling in guinea pigs (GP) with chronic allergic inflammation. Animals received seven inhalations of ovalbumin (1–5 mg/mL-OVA group) or normal saline (NS group). OT was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st ovalbumin inhalation (OT1 group) or after the 4th (OT2 group). The induction of OT in sensitized animals decreased the elastance of respiratory system (Ers) response after both antigen and methacholine challenges, peribronchial edema formation, eosinophilic airway infiltration, eosinophilopoiesis, and airways collagen and elastic fiber content compared to OVA group (P < 0.05). The number of mononuclear cells and resistance of respiratory system (Rrs) responses after antigen and methacholine challenges were decreased only in OT2 group compared to OVA group (P < 0.05). Concluding, our results show that inducing OT attenuates airway remodeling as well as eosinophilic inflammation and respiratory system mechanics.

Introduction

Asthma results from an allergen-driven Th2 (T helper 2) response in which inflammation and airway remodeling have an important clinical significance, contributing to the irreversibility of lung function alterations (Brown et al., 2006, Yamauchi, 2006, Southam et al., 2007). Airway remodeling represents a dynamic process that may lead to structural changes in the airways in asthma, including: subepithelial fibrosis, mucous metaplasia, wall thickening, myocyte hypertrophy and hyperplasia, myofibroblast hyperplasia, vascular proliferation, and changes in the extracellular matrix such as deposition of collagen fiber and alterations in the airway elastic fibers (Vignola et al., 2003, Mauad et al., 2004, Prado et al., 2006). Many authors had evaluated the lung remodeling in asthma experimental models and they found that chronic experimental models of allergic inflammation induces an increase in collagen and elastic fibers content in both airways and lung parenchyma (Tanaka et al., 2001, Palmans et al., 2002, Prado et al., 2005b, Prado et al., 2006).

Oral tolerance has classically been defined as the specific suppression of cellular and/or humoral immune response to an antigen by prior administration of the antigen by the oral route (Faria et al., 2005). There are two primary effectors mechanisms of oral tolerance: the induction of regulatory T cells that mediate active suppression and the induction of clonal anergy or deletion (Garside et al., 2004, Dubois et al., 2005, Faria and Weiner, 2005).

Strategies to selectively induce oral tolerance (OT) to specific antigens have been tested in humans and in animal models of allergic diseases (Faria and Weiner, 2005). It may be considered a preventive or a therapeutic strategy in asthma, if the oral antigen is initiated before or concomitantly with the primary immunization or after the establishment of inflammatory and allergic responses, respectively (Chung et al., 2002, Keller et al., 2006, Nakashima et al., 2008).

Experimental oral tolerance studies have shown the suppression of Th2 allergic response, decreasing the number of eosinophils in the lung and bone marrow, as well as the production of specific antibodies, the production of mucus and Th2 cytokines in the lung and bronchial hyperresponsiveness (Russo et al., 1998, Russo et al., 2001, Chung et al., 2002, Futata et al., 2006, Keller et al., 2006). However, the effects of OT on airway remodeling, particularly collagen and elastic fibers content, have not been investigated.

Our primary aim was to assess whether extracellular matrix remodeling in airway walls may be attenuated by OT induction either using a preventive or a therapeutic approach in an animal model of chronic allergic inflammation. We also studied pulmonary hyperresponsiveness and airway inflammatory response.

Section snippets

Methods

The animals weighed 300–350 g initially and were aged about three weeks old. All animals received humane care in compliance with the Guide for Care and Use of Laboratory Animals National Institutes of Health, publication 85–23, revised 1985, and the Local Ethical Committee approved the study.

Inhalation time

During the first four ovalbumin solution inhalations, we did not observe signs of respiratory distress in any guinea pig studied. The OVA group (mean ± standard error: 296.75 ± 63.28; 361.70 ± 64.07; 240.75 ± 31.49 s for 5th, 6th and 7th inhalation, respectively) stayed less time in contact to antigen until respiratory distress occurred presenting a lower inhalation time compared to NS group (900 ± 00 for all inhalations, P < 0.001 for 5th, 6th and 7th inhalation). Both OT treated animals (OT1: 642.56 ± 

Discussion

In the present study, we observed that induction of OT, either as a preventive or as a therapeutic strategy (OT1 and OT2 groups, respectively) reduced airway collagen and elastic fibers content in GP induced by chronic allergic inflammatory stimuli. These findings were associated with an attenuation of IgG1 antibody responses, eosinophilic recruitment, eosinophilopoiesis, peribronchial edema formation and pulmonary hyperresponsiveness in both experimental protocols of OT that were tested in

Acknowledgements

This work was supported by following Brazilian scientific agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Laboratório de Terapêutica Experimental I (LIM20-HC-FMUSP). We would like to thank to Prof. Paulina Sannomiya for the carefully revision of the manuscript and to Beatriz M. Saraiva Romanholo, Adenir Perini, Sandra de Moraes Fernezlian, and Esmeralda Meristene for skillful technical assistance.

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