Investigations on the IL-13 signalling along the airway tree-implications on mucus production in allergic asthma?

Introduction: Allergic asthma is the most common chronic inflammatory disease worldwide and is clinically characterized by a variable degree of broncho-obstruction. Increased mucus production is a critical factor impairing lung function. In acute and chronic mouse models of allergic asthma hyperplasia of mucus producing goblet cells (GC) was found in proximal but not in distal airways although secretion of interleukin (IL)-13, the main trigger of mucus production, was significantly elevated along the entire airway tree. The aim of the current study was to identify the part of the IL-13 signalling pathway that detains TH2 cell derived IL-13 from inducing GC hyperplasia in distal airways.

Methods: BALB/c mice were sensitized with OVA/Alum and subsequently challenged with OVA for one (acute) or twelve weeks (chronic). To assess lung morphology, lungs were fixed under constant pressure with 4% paraformaldehyde followed by paraffin embedding. Systemic uniform samples were stained with periodic acid Schiff (PAS) to analyse mucus production. Lungs were inflated with RNAlater® to microdissect proximal and distal airways for gene expression analysis.

Results: Quantitative RT-PCR revealed similar expression levels of the IL-13 receptor alpha 2 (IL-13Rα2) and IL-4Rα in the acute and chronic asthma model along the airway tree. Interestingly, the expression of IL-13Rα1 is lower in distal airways in both acutely (1.5-fold) and chronically (1.5-fold) challenged mice as well as in PBS-treated control animals (1.3-fold). Dramatically, the expression of SAM pointed domain-containing ETS transcription factor (Spdef), a transcription factor down-stream of the IL-13-induced IL-13Rα1 signalling cascade required for GC metaplasia, was rarely induced in distal airways but extensively in proximal airways in the acute (10-fold) and chronic model (4-fold). Along with this, Spdef-regulated FoxA3 showed higher induction in proximal compared to distal airways in the acute (7.6 vs. 4.3-fold) and the chronic (3.9 vs. 2.5-fold) asthma model.

Discussion: Thus, distal airways might be protected from mucus plugging and impaired ventilation of the attached alveoli not only by the diminished expression of IL-13Rα1 but also by being less sensitive towards IL-13 induced signalling.