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
Accepted on May 17, 2005
Differential Proteolytic Enzyme Activity in Eosinophilic and Neutrophilic Asthma
Jodie L Simpson1, Rodney J Scott2, Michael J Boyle3, and Peter G Gibson1*
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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