Published ahead of print on May 18, 2005, doi:10.1164/rccm.200503-369OC Am. J. Respir. Crit. Care Med., Volume 172, Number 5, September 2005, 559-565 A more recent version of this article appeared on September 1, 2005
Submitted on March 8, 2005 Differential Proteolytic Enzyme Activity in Eosinophilic and Neutrophilic AsthmaJodie L Simpson1,1 School of Medical Practice and Population Health, The University of Newcastle, Callaghan, NSW, Australia; Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter Medical Research Institute, New Lambton, NSW, Australia, 2 Medical Genetics, School of Biomedical Sciences, The University of Newcastle, Hunter Medical Research Institute, Callaghan, NSW, Australia, 3 School of Medical Practice and Population Health, The University of Newcastle, Callaghan, NSW, Australia; Department of Immunology and Infectious Diseases, John Hunter Hospital, Hunter Medical Research Insitute, New Lambton, NSW, Australia * To whom correspondence should be addressed. E-mail: peter.gibson{at}hnehealth.nsw.gov.au.
Rationale: Asthma is characterised by both chronic inflammation and remodelling of the airways. Proteases are important mediators of inflammation, cytokine activation and tissue remodelling. Objectives: This study investigates matrix metalloproteinase-9 and neutrophil elastase enzyme activity in the sputum of subjects with different inflammatory phenotypes of asthma (eosinophilic, neutrophilic and paucigranulocytic asthma) and in healthy controls. Methods and Measurements: Non-smoking adults with asthma and healthy controls underwent hypertonic saline challenge and sputum induction. Selected sputum portions were dispersed with dithiothreitol and assayed for matrix metalloproteinase-9 and neutrophil elastase enzyme activity. Main Results: Subjects with eosinophilic asthma had significantly more active matrix metalloproteinase-9 (39ng/mL) compared to neutrophilic asthma (10ng/mL) and controls (2.5ng/mL, p<0.01). Although there were high levels of total matrix metalloproteinase-9 in neutrophilic asthma (5273ng/mL), most (>99%) was inactivated (and bound to TIMP-1). In neutrophilic asthma more subjects had neutrophil elastase activity (39%) compared to both healthy controls (0%), subjects with eosinophilic asthma (6%) or paucigranulocytic asthma (0%, p<0.05). There were strong and consistent positive correlations between IL-8, neutrophils and proteolytic enzymes. Matrix metalloproteinase-9 was inversely correlated with neutrophil elastase (r=-0.93). Conclusions: Proteolytic enzyme activity in asthma is dependent on the underlying inflammatory phenotype and is differentially regulated with matrix metalloproteinase-9 activity a feature of eosinophilic inflammation, and active neutrophil elastase in neutrophilic inflammation. Key words: Sputum, Inflammation, Peptide hydrolases
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