# Activated Neutrophilic Exosome as Biomarker and Therapeutic Target in COPD

> **NIH NIH K08** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $164,916

## Abstract

Project Summary/Abstract:
Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the
world, is a chronic inflammatory disease thought to be driven at least in part by
derangements of protease-antiprotease balance. Recent discoveries have suggested
that proteases such as neutrophil elastase (NE) can be associated with exosomes
released by neutrophils (PMNs). Exosomes are nanovesicles released by the cell into
the environment. NE is enzymatically active when associated with exosomes yet it is
markedly resistant to inhibition by α-1 antitrypsin (α-1AT) in this form. Exosomal NE is
several log-fold more potent in causing COPD in mouse models than soluble NE, and
the exosomes themselves are able to traverse tissue planes and bind to structural
proteins in the lung such as type I collagen, focusing the proteolysis upon its substrate.
Importantly, exosomes derived from PMNs that are capable of causing NE-dependent
alveolar destruction in mice have been found in bronchoalveolar lavage fluid (BALF) of
subjects with COPD, but not healthy controls. Because of these findings, it seems likely
that this exosome-associated form of NE may be more important to extracellular matrix
destruction (and thus COPD pathogenesis) than conventionally measured soluble NE.
This research project will quantify the PMN-derived, NE+ exosome burden within three
well-phenotyped cohorts of subjects with COPD as well as non-obstructed never
smoker and current/former smoker control subjects. Furthermore, the PMN-derived,
NE+ exosome profile of sputum and serum will be assessed to define the biomarker
utility of this process using less invasively derived specimens than BALF. These
findings will be correlated with various clinically validated measures of COPD disease
progression, symptom burden as well as disease sub-phenotype and will be correlated
with development of COPD among subjects at risk for this disease. Moreover, this
project will develop and optimize an animal model of pathogenic exosome transfer,
delineate the mechanism of NE binding to the PMN exosome surface, and advance
rational strategies designed to interrupt exosome pathogenicity. These studies will form
the foundation for the use and further study of PMN-derived, NE+ exosomes as
biomarkers of disease activity and potential therapeutic targets.

## Key facts

- **NIH application ID:** 10404995
- **Project number:** 5K08HL148514-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Derek Russell
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $164,916
- **Award type:** 5
- **Project period:** 2020-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404995

## Citation

> US National Institutes of Health, RePORTER application 10404995, Activated Neutrophilic Exosome as Biomarker and Therapeutic Target in COPD (5K08HL148514-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10404995. Licensed CC0.

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