Pediatric Pulmonology 45:860–868 (2010) Original Articles Association of Airway Cathepsin B and S With Inflammation in Cystic Fibrosis S.L. Martin, PhD, 1 * K.L. Moffitt, PhD, 1 A. McDowell, PhD, 2 C. Greenan, PhD, 1 R.J. Bright-Thomas, MD, 3 A.M. Jones, MD, 3 A.K. Webb, MD, 3 and J.S. Elborn, MD 2 Summary. Irreversible tissue damage within the cystic fibrosis (CF) lung is mediated by proteolytic enzymes during an inflammatory response. Serine proteinases, in particular neutrophil elastase (NE), have been implicated, however, members of the cysteine proteinase family mayalso be involved. The aim of this study was to determine cathepsin B and S levels in cystic fibrosis (CF) sputum and to assess any relationship to recognized markers of inflammation such as sputum NE, interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-a), urine TNF receptor 1 (TNFr1), plasma IL- 6, and serum C-reactive protein (CRP). Proteinase activities were measured in the sputum of 36 clinically stable CF patients using spectrophotometric and fluorogenic assays. Immunoblots were also used to confirm enzyme activity data. All other parameters were measured by ELISA. Patients had a mean age of 27.2 (8.2) years, FEV. of 1.6 (0.79) L and BMI of 20.7 (2.8). Both cathepsin B and S activities were detected in all samples, with mean concentrations of 18.0 (13.5) mg/ml and 1.6 (0.88) mg/ml, respectively, and were found to correlate not only with each other but with NE, TNF-a and IL-8 (in all cases . < 0.05). Airway cathepsin B further correlated with circulatory IL-6 and CRP, however, no relationship for either cathepsin was observed with urine TNFr1. This data indicates that cathepsin B and S may have important roles in the pathophysiology of CF lung disease and could have potential as markers of inflammation in future studies. Pediatr Pulmonol. 2010; 45:860–868. ß 2010 Wiley-Liss, Inc. Key words: cathepsin; cysteine proteinase; cystic fibrosis; inflammation; neutrophil elastase. Funding source: none reported INTRODUCTION Irreversible tissue damage within the cystic fibrosis (CF) lung is mediated by proteolytic enzymes secreted primarily by accumulating macrophages and neutrophils during the inflammatory response to chronic pulmonary infection. 1,2 To date, most attention has focused on the role of the serine proteinase, neutrophil elastase (NE) with few studies investigating the role that other classes of enzymes play in the pathogenesis of airways disease. 3–5 Many of the lysosomal cysteine proteinases are potent elastinolytic and collagenolytic enzymes which are released in active form by stimulated macrophages during the inflammatory process. 6 Cathepsin release is also detected from mast cells (cathepsin L), 7 smooth muscle cells (cathepsins S and K), 8 fibroblasts (cathepsin B) and tumor cells (cathepsins B, L, and S), 9 as they are involved in matrix remodeling and the regulation of both the innate and adaptive immune response. 10 They are not The authors declare that they have no competing interests. 1 School of Pharmacy, Queen’s University, Belfast, UK. 2 School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast, Northern Ireland, UK. 3 Manchester Adult Cystic Fibrosis Centre, South Manchester University Hospitals NHS Trust, Manchester, UK. *Correspondence to: S.L. Martin, PhD, School of Pharmacy, Queen’s University Belfast, McClay Research Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. E-mail: l.martin@qub.ac.uk Received 2 July 2009; Revised 31 January 2010; Accepted 1 February 2010. DOI 10.1002/ppul.21274 Published online 14 July 2010 in Wiley Online Library (wileyonlinelibrary.com). ß 2010 Wiley-Liss, Inc.