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


OBJECTIVE
We sought to determine whether SR asthma is accompanied by decreased airflow reversibility and could lead to airway remodeling.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.


CONCLUSIONS
SR asthma might lead to irreversible airways disease.
Goleva
Elena
E
Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 802060, USA.
Hauk
Pia J
PJ
Boguniewicz
Juri
J
Martin
Richard J
RJ
Leung
Donald Y M
DY
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D001249:Asthma / Q000188:drug therapy* / Q000473:pathology*; D001980:Bronchi / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use; D004351:Drug Resistance; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000032:analysis / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D013147:Spirometry; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D001993:Bronchodilator Agents; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; D003907:Dexamethasone; D019272:Leukocyte Elastase; D020780:Matrix Metalloproteinase 9