# Assessing the role of metabolism in monocyte to macrophage differentiation in pulmonary fibrosis

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2021 · —

## Abstract

Project Summary
Idiopathic Pulmonary Fibrosis (IPF) has a prognosis worse than most cancers, with only 20-30 percent of patients
surviving 5 years after diagnosis. The pathophysiology in IPF relates to dysregulated repair after injury to the
alveolo-capillary though the mechanisms that link alveolar capillary membrane injury with fibroblast activation
and disordered repair are incompletely understood. In a recent publication we provide clear genetic evidence
that alveolar macrophages are key effector cells in the development of fibrosis in mice which was validated in
human alveolar macrophages obtained from pulmonary fibrosis patients. We reported that monocytes recruited
to the lung during injury and fibrosis express unique markers and change their morphology to resemble alveolar
macrophages. Using combined genetic lineage tracing, a targeted genetic strategy and transcriptomic analysis
(RNA-Seq) of flow-sorted myeloid populations we showed that “monocyte-derived alveolar macrophages” and
“tissue-resident alveolar macrophages” play distinct roles in the development of lung fibrosis. Critically,
genetically deleting monocyte derived alveolar macrophages independent of tissue resident alveolar
macrophages reduced the severity of bleomycin induced fibrosis. Our results are consistent with findings from
others who have suggested that the differentiation from monocytes into tissue-resident macrophages is driven
by epigenetic changes in response to cues from the local tissue microenvironment. Because the process of
monocyte to alveolar macrophage differentiation is specific to the lung, therapies that target this process after a
monocyte has been recruited into the lung are likely to avoid the systemic toxicity associated with systemic
monocyte depletion. One feature of the bleomycin lung fibrosis model is the spontaneous resolution of fibrosis
over 2-3 months, which does not recapitulate IPF in which continuous progression of lung fibrosis is the norm.
However, we have and others have shown that the asbestos mouse model of lung fibrosis does demonstrate
progressive fibrosis and thus may more accurately recapitulate human IPF. In order to provide a more compelling
rationale for targeting monocyte-macrophage differentiation as a therapeutic target for IPF, we plan to address
three important questions raised by our data in our renewal application. First, do monocyte-derived alveolar
macrophages play a similar role in asbestos mouse models of non-resolving lung fibrosis? We have already
generated preliminary data supporting this hypothesis. As part of these experiments, we will perform single cell
transcriptomics (DROP-Seq) to determine whether the expression of pro-fibrotic genes in monocyte-derived
alveolar macrophages is attributable to a subpopulation of cells. Second, can the deletion of monocyte-derived
alveolar macrophages promote the resolution of fibrosis after it is established? Third, can we use our
transcriptomic data to inform strategies to ...

## Key facts

- **NIH application ID:** 10039497
- **Project number:** 5I01CX001777-10
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** GR Scott Budinger
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2010-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10039497

## Citation

> US National Institutes of Health, RePORTER application 10039497, Assessing the role of metabolism in monocyte to macrophage differentiation in pulmonary fibrosis (5I01CX001777-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10039497. Licensed CC0.

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