Airway remodeling and lack of bronchodilator response in steroid-resistant asthma

Abstract

Steroid-resistant (SR) asthma is characterized by airway inflammation that fails to resolve despite treatment with corticosteroids, raising concerns that resistance to steroid therapy in asthma could lead to airway remodeling. We sought to determine whether SR asthma is accompanied by decreased airflow reversibility and could lead to airway remodeling. Spirometric results were evaluated for 40 asthmatic patients defined as having SR or steroid-sensitive (SS) asthma on the basis of a 1-week course of oral prednisone. Twenty-three asthmatic patients underwent bronchoscopy with collection of bronchoalveolar lavage (BAL) fluid to analyze markers of airway remodeling in BAL fluid and cells. Prednisone significantly improved FEV(1) percent predicted in SS asthma (62.0% +/- 10.9% [mean +/- SD] to 79.4% +/- 11.3%, P < .001) but not in SR asthma (66.9% +/- 10.0% to 65.9% +/- 12.1%). The bronchodilator response was significantly greater in the SS than in the SR group (Delta FEV(1) percent predicted, 33.5% +/- 22.5% vs 15.2% +/- 7.9%; P = .001), regardless of inhaled corticosteroid use. No difference in amounts of matrix metalloproteinase (MMP) 9, PMN elastase, or vascular endothelial growth factor was found in BAL fluid from both groups. Tissue inhibitor of metalloproteinases (TIMP) 1 levels were, however, significantly less in BAL fluid of patients with SR asthma compared with those in patients with SS asthma (921.9 +/- 313.4 vs 2267.0 +/- 456.8 pg/mL, P < .05), resulting in significantly higher MMP-9/TIMP-1 ratios in the BAL fluid of patients with SR asthma (0.24 +/- 0.04 vs 0.11 +/- 0.03, P < .01). Finally, dexamethasone treatment induced TIMP-1 mRNA in BAL fluid cells from patients with SS asthma (P < .01) but not in cells from patients with SR asthma. Bronchodilator reversibility is impaired in SR asthma and is associated with a shift in MMP-9/TIMP-1 ratio caused by inability of steroids to enhance TIMP-1 production, potentially promoting proteolytic activity in airways of patients with SR asthma and contributing to chronic airway remodeling. SR asthma might lead to irreversible airways disease.