# Neutrophil Exosomes: New Pathogenic Entities in COPD

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2022 · —

## Abstract

COPD is a chronic inflammatory pulmonary condition which the 3rd leading cause of death in the United
States and has significant impact on the US Veteran and active military population. Despite its
prevalence and increased attributable morbidity/mortality, there are no specific COPD therapeutics
which alter the natural history of the disorder. Our group and others have provided extensive evidence
of the importance of proteolytic damage as a critical component to the progression of COPD. However,
our ability to understand how proteases bypass the robust antiprotease shield within the lung is poorly
understood. Here, we examine a new pathogenic entity, the neutrophil-derived exosome, which
expresses the protease neutrophil elastase (NE) on its surface. We provide preliminary data
demonstrating these exosomes have active NE enzymatic activity, capable of degrading components of
the lung extracellular matrix (ECM). Importantly, we highlight that exosome-associated NE is resistant
to its naturally occurring antiprotease, alpha-1 antitrypsin (A1AT), and can lead to fulminant
emphysema when intratracheally administered in vivo. For this proposal, we will build on these seminal
observations, first by examining the impact of smoke to induce the release of these proteolytic
exosomes from PMNs (Specific Aim 1a) and then examining the antiprotease resistance of exosomes
isolated from COPD and non-COPD subjects, with a focus of inducing NE disassociation from these
exosomes to enhance endogenous antiprotease sensitivity (Specific Aim 1b). Next, we will use
bronchoalveolar lavage (BAL) samples from 6-month smoking mouse model, isolate PMN-derived
exosomes, and intratracheally deliver these into naïve mice to induce emphysema, inhibiting these
effects via NE disassociation (Specific Aim 2). Finally, we will examine a cohort of COPD subjects
(current or former smokers) and non-COPD subjects (smokers and never smokers) to determine the
expression of NE-associated exosomes in these cohorts and stability of these measurements over time
(Specific Aim 3). The successful completion of these aims will lead to an increased understanding of
the PMN exosome as a critical pathogenic entity in COPD, with improved understanding of the
downstream effects of its unfettered protease activity. Importantly, these studies will likely result in the
development of a new biomarker and potential new therapeutic approaches for the treatment of
Veterans who are diagnosed with COPD.

## Key facts

- **NIH application ID:** 10480885
- **Project number:** 5I01CX001969-03
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** AMIT GAGGAR
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480885

## Citation

> US National Institutes of Health, RePORTER application 10480885, Neutrophil Exosomes: New Pathogenic Entities in COPD (5I01CX001969-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10480885. Licensed CC0.

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