Compartmental and Temporal Dynamics of Chronic Inflammation and Airway Remodelling in a Chronic Asthma Mouse Model

Mohammed Alrifai,Holger Garn,Tanja Dicke,Harald Renz,Ayse Kılıç,Melanie L Conrad,Leigh M Marsh,Heinz Fehrenbach

doi:10.1371/journal.pone.0085839

Abstract

BackgroundAllergic asthma is associated with chronic airway inflammation and progressive airway remodelling. However, the dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly understood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes.MethodsUsing BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and presence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of bronchoalveolar and peribronichal inflammatory cell infiltrate, goblet cell hyperplasia, collagen deposition and smooth muscle thickening.ResultsChronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and smooth muscle thickening). After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and collagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only observed after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the development of lung inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth muscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy was discontinued.ConclusionsUtilising a chronic model of experimental asthma we have shown that repeated allergen exposure induces reversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in inhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective in preventing smooth muscle hypertrophy.

Highlights

Human bronchial asthma is a chronic inflammatory disease of the airways that is characterized by chronic airway inflammation, airway hyperresponsiveness (AHR), and airway remodelling [1,2,3]
In the bronchoalveolar lavage fluid (BALF), peak cell infiltration was observed at 6 weeks of OVA challenge, which steadily decreased until 12 weeks and remained at almost baseline levels (Figure 2A and Figure S1)
Comparison of periodic acidSchiff reagent (PAS)-stained lung sections from chronically OVA treated mice revealed that,45% of all cells lining the bronchial airways throughout the whole observation period were goblet cells

Summary

Introduction

Human bronchial asthma is a chronic inflammatory disease of the airways that is characterized by chronic airway inflammation, airway hyperresponsiveness (AHR), and airway remodelling [1,2,3]. Current anti-inflammatory treatment of asthma is predominately based on the use of inhaled corticosteroids (ICS). These drugs are highly effective in preventing life threatening consequences of asthma [7], their effect is limited in modulating airway remodelling [8]. The therapeutic potential of budesonide has extensively been studied in models of acute allergic inflammation but only a few studies have investigated efficacy on established airway remodelling and chronic asthma [10,11]. We have investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes

Methods

Results

Conclusion