Introduction Serine trypsin-like (TL) proteases, which are excessively active in CF airways, promote activation of the epithelial sodium channel (ENaC) and airways dehydration; a key initiating factor for CF lung disease pathogenesis. Furthermore TL-proteases enhance mucin gene expression and mucus hypersecretion, yet whether there is any relationship between the activity of these enzymes and CF pulmonary disease is unknown.Objectives The primary objective of the current investigation was to determine whether TL-protease activity, measured in adult CF sputum sol, correlates with lung disease and patient outcome (survival). A secondary objective was to compare the strength of any relationships observed with that of neutrophil elastase (NE), an established protease biomarker.Methods In this cross sectional retrospective study we analysed CF sputum sol collected from 30 clinically stable adult CF patients. Protease activity was measured by monitoring the hydrolysis of peptide-based substrates. Biomarkers of inflammation (IL-8 and TNF-α) were measured by ELISA. Lung function was assessed by spirometry (FEV1). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis.Results TL-protease activity inversely correlated with lung function (FEV1) (r = −0.4, p = 0.031) however, no relationship with IL-8 and TNFα was observed. In contrast, NE was found to correlate with IL-8: r = 0.7, p < 0.001 and TNFα: r = 0.7, p < 0.001 but showed no relationship with lung function, indicating that these serine proteases play very distinct roles within the disease process. Kaplan-Meier analysis demonstrated significantly reduced survival for those individuals with above median TL-protease activity. Levels of NE activity showed no relationship with patient survival. Using a multivariate Cox regression analysis (adjusted for age and BMI) a significantly increased mortality hazard (HR 1.028, 95% CI: 1.007–1.049; p = 0.009) was also identified. These findings are supported by analysis of a validation cohort consisting of samples collected from a separate cohort of 33 adult CF patients.Conclusions TL-protease activity inversely correlates with lung function and patient survival. As such tryptic activity may warrant consideration when modelling CF survivorship and should be investigated further as a biomarker of CF lung disease and as a potential therapeutic target.
|Issue number||Suppl 3|
|Publication status||Published - 15 Dec 2016|
|Event||British Thoracic Society, Winter Meeting - QEII Centre, Westminster, London, United Kingdom|
Duration: 07 Dec 2016 → 09 Dec 2016