Project Summary
Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disease believed to be driven
by protease-antiprotease imbalance. The mechanisms leading to this imbalance have yet to be fully
understood. Recent work has suggested that exosomes (small nanovesicles released by cells) from
activated neutrophils (PMNs) are coated in neutrophil elastase (NE) from degranulated PMNs and this
exosome associated NE renders it protected from its native antiprotease, alpha-1-antitrypsin (a1AT).
This resistance to a1AT makes exosome associated NE several log-fold more potent in causing a COPD
disease-like phenotype in mouse models than free NE in solution. These PMN exosomes can bind to
type I collagen and degrade structural extracellular matrix (ECM) proteins. Of bigger significance, these
PMN derived NE+ exosomes can cause alveolar destruction in a mouse model and these NE+ exosomes
can be found in the BALF of COPD patients, but not healthy never smoker controls, indicating an
important role for exosome associated NE in COPD disease progression. This grant will identify the
mechanism of NE association to the surface of PMN exosomes as well as focusing on molecules to
disrupt this association, rendering the NE susceptible to a1AT inactivation. Furthermore, this grant will
develop a smoking mouse model of NE+ PMN exosome production and disease transfer to naïve mice,
effectively creating a mouse-mouse transfer model of disease. Additionally, this grant will correlate the
presence of PMN NE+ exosomes in COPD patient BALF with other significant parameters of COPD
severity. Moreover, PMN derived NE+ exosomes from other, less invasive patient fluid samples, serum
and sputum, will be quantified and their ability to transfer disease to mouse model of COPD will be
compared to those from patient BALF. Additionally, substances studied that can dissociate NE from the
exosome surface can be developed into potential therapeutic targets.