TAILS proteomics reveals dynamic changes in airway proteolysis controlling protease activity and innate immunity during COPD exacerbations

• DOI: 10.1152/ajplung.00175.2018
• Publication Date: 2018-10-04T09:02:25Z
• Authors: Brendan Mallia-Mi...; Antoine Dufour; Christopher Philp; Nestor Solis; Theo Klein; Marlies Fischer; Charlotte E. Bolton; Steven Shapiro; Christopher M. Ov...; Simon R. Johnson
• Keywords: Proteolysis; Neutrophil elastase; Protease inhibitor (pharmacology)

Dysregulated protease activity is thought to cause parenchymal and airway damage in chronic obstructive pulmonary disease (COPD). Multiple proteases have been implicated COPD, identifying their substrates may reveal new mechanisms treatments. However, as interact with many that be inhibitors or themselves, these webs of interactions make the wider consequences therapeutically targeting difficult predict. We therefore used a systems approach determine COPD airways. Protease were determined by proteomics using terminal amine isotopic labeling (TAILS) methodology paired sputum samples during stable exacerbations. specific protein degradation assessed Western blotting, substrate assays, ex vivo cleavage assays. Two hundred ninety-nine proteins identified human sputum, 125 which proteolytically processed, including proteases, inhibitors, mucins, defensins, complement other innate immune proteins. During exacerbations, neutrophils neutrophil increased more cleaved, particularly at multiple sites, consistent inactivation. different Exacerbations associated increasing elastase processing substrates, secretory leukocyte inhibitor. Proteolysis regulates processes airways differs The complexity protease, inhibitor, networks makes effect hard predict should cautiously.