Elastin synthesis and degradation in the airway and lung parenchyma contribute to airway mechanics, including airway patency and elastic recoil. Interleukin (IL)-13 mediates many features of asthma pathobiology, including airway remodeling, but the effects of IL-13 on elastin architecture in the airway wall are not known. We hypothesized that IL-13 modulates elastin expression in airway fibroblasts from subjects with allergic asthma.
25 subjects with mild asthma (FEV1: 89 ± 3% pred) and 30 normal controls (FEV1: 102 ± 2% pred) underwent bronchoscopy with endobronchial biopsy. Elastic fibers were visualized in airway biopsy specimens using Weigert's resorcin-fuchsin elastic stain. Airway fibroblasts were exposed to IL-13, a pan-matrix metalloproteinase (MMP) inhibitor (GM6001), specific inhibitors to MMP-1, -2, -3 and -8, and combinations of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours. Elastin (ELN) expression as well as MMP secretion and activity were quantified.
Elastic fiber staining of airway biopsy tissue was significantly associated with methacholine PC20 levels in asthma patients. IL-13 significantly suppressed ELN expression in asthmatic airway fibroblasts as compared to normal controls. The effect of IL-13 on ELN expression was significantly correlated with post-bronchodilator FEV1/FVC in asthmatic patients. MMP inhibition significantly stimulated ELN expression in asthma as compared to normal controls. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed the IL-13-induced suppression of ELN expression.
In asthma, MMP-1 and MMP-2 mediate IL-13-induced suppression of ELN expression in airway fibroblasts.