# Mechanism of pathogenic macrophage activation in emphysema

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $597,019

## Abstract

Mechanism of pathogenic macrophage activation in emphysema
Summary
Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the U.S. and its prevalence
is increasing globally. Emphysema, a key component of COPD most commonly associated with cigarette
smoking, is defined by an irreversible loss of lung surface area and decrements in gas exchange that arise
from progressive alveolar wall destruction. While elements that contribute to the initiation and pathogenesis of
emphysema have been identified, including recurrent inflammation, oxidative stress, excess protease activity,
cell death and genetics, we still lack clear mechanisms that would provide novel targets to slow or stop disease
progression during or after smoking cessation. In this proposal, we have identified a novel role for pathologic
macrophages in causing the progressive damage in emphysema. Strong preliminary data shows that IL-33
remains elevated in the lung after acute lung damage and is associated with an increase in Pathogenic Lung
Macrophages (PLM) that have an altered M2 phenotype. Furthermore, our data also suggest that IL-17A is
critical for this transition into PLM that work against the normal healing function of M2 macrophages. Although
both IL-17A and IL-33 have been found in patients with COPD, little is known about how they impact the
mechanism of progressive tissue destruction. Experiments will test a novel 2-step mechanism for lung
macrophage activation in which IL-33 and IL-13, generated as a consequence of epithelial cell damage, initially
result in conventional M2 activation, followed by second signal from IL-17A that modifies the macrophages to
the PLM that mediate alveolar destruction. Our proposal is designed to test the central hypothesis that IL-33,
IL-13 and IL-17A work together to promote the generation of pathogenic lung macrophages that play a
principal role in progressive emphysema. Once the basic mechanisms are better understood in our first two
aims, the third aim will test the hypothesis that the known plasticity of macrophages can be exploited to devise
a therapeutic strategy to blunt or stop the progression of emphysema. The insights obtained from these
studies should provide novel mechanistic insights and new potential therapeutic targets to limit the accelerated
loss of lung function in humans with COPD.

## Key facts

- **NIH application ID:** 9857065
- **Project number:** 5R01HL140623-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Wayne Mitzner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $597,019
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857065

## Citation

> US National Institutes of Health, RePORTER application 9857065, Mechanism of pathogenic macrophage activation in emphysema (5R01HL140623-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857065. Licensed CC0.

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