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Differential Proteolytic Enzyme Activity in Eosinophilic and Neutrophilic Asthma

School of Medical Practice and Population Health, and Medical Genetics, School of Biomedical Science, Hunter Medical Research Institute, The University of Newcastle, Callaghan; Department of Respiratory and Sleep Medicine, and Immunology and Infectious Diseases, Hunter Medical Research Institute, John Hunter Hospital, New Lambton, Australia

Correspondence and requests for reprints should be addressed to Prof. Peter G. Gibson, Level 3, HMRI, John Hunter Hospital, Locked Bag 1, Hunter Region Mail Centre, Newcastle, NSW 2310, Australia. E-mail: peter.gibson{at}hnehealth.nsw.gov.au

Rationale: Asthma is characterized by both chronic inflammation and remodeling of the airways. Proteases are important mediators of inflammation, cytokine activation, and tissue remodeling. Objectives: This study investigated matrix metalloproteinase-9 (MMP-9) and neutrophil elastase (NE) enzyme activity in the sputum of subjects with different inflammatory phenotypes of asthma (eosinophilic, neutrophilic, and paucigranulocytic asthma) and in healthy control subjects. Methods and Measurements: Nonsmoking adults with asthma and healthy control sujects underwent hypertonic saline challenge and sputum induction. Selected sputum portions were dispersed with dithiothreitol and assayed for MMP-9 and NE enzyme activity. Main Results: Subjects with eosinophilic asthma had significantly more active MMP-9 (39 ng/ml) compared with those with neutrophilic asthma (10 ng/ml) and control subjects (2.5 ng/ml, p < 0.01). Although there were high levels of total MMP-9 in neutrophilic asthma (5,273 ng/ml), most (> 99%) was inactivated (and bound to tissue inhibitor of metalloproteinase-1). In neutrophilic asthma, more subjects had NE activity (39%) compared with both healthy control subjects (0%), subjects with eosinophilic asthma (6%), or subjects with paucigranulocytic asthma (0%, p < 0.05). There were strong and consistent positive correlations between interleukin-8, neutrophils, and proteolytic enzymes. MMP-9 was inversely correlated with NE (r = –0.93). Conclusions: Proteolytic enzyme activity in asthma is dependent on the underlying inflammatory phenotype and is differentially regulated with MMP-9 activity a feature of eosinophilic inflammation, and active NE in neutrophilic inflammation.

Key Words: inflammation • peptide hydrolases • sputum

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