Sunday, December 22, 2024
12/22/2024
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 (α1AT). This resistance to α1AT 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 α1AT 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.
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