Pathophysiological Changes in Asthma Induced by Weight Loss

Background: Elastin makes important contributions to airway wall biomechanics, collapsibility, and elastic recoil. Loss of elastic recoil has been shown in asthma; elastolysis has been implicated as an etiology. We have demonstrated that IL-13 suppresses elastin expression in airway fibroblasts isolated from subjects with asthma. IL-13 induces matrix metalloproteinases, which can affect mediators of elastin transcription. We sought to determine the effect of matrix metalloproteinase (MMP) inhibition on elastin gene regulation. Objective: To determine whether IL-13 and MMP inhibition modulate elastin mRNA expression by airway fibroblasts isolated directly from subjects with asthma. Methods: In an ongoing study, 15 subjects with mild asthma (FEV1 78 6 13% predicted) and 15 normal control subjects (FEV1 107 6 10% predicted) underwent bronchoscopy with endobronchial biopsy. Tissue specimens were placed in Dulbecco’s modified Eagle’s medium with fetal bovine serum and antibiotics until confluence, followed by incubation in serum-free media for 48 hours. Experimental conditions included negative controls, as well as IL-13 (10 and 50 ng/ml) in the presence and absence of the MMP inhibitor GM6001 (10 mM). Elastin mRNA was extracted and quantified by RT-PCR. Results: IL-13 (10 and 50 ng/ml) diminished airway fibroblast elastin mRNA expression compared with negative controls (P , 0.0001 for both concentrations). However, the addition of a pan-MMP inhibitor induced elastin transcription by 2.8-fold (after 24 h of incubation), despite the presence of IL-13. Conclusion: We show that in human asthma, IL-13 suppression of elastin transcription is reversed by MMP inhibition.