# Lung Macrophage Programming in Acute Lung Injury

> **NIH NIH R35** · NATIONAL JEWISH HEALTH · 2020 · $556,324

## Abstract

PROJECT SUMMARY
Acute inflammatory lung diseases affect over 450 million people worldwide each year. Pathologic hallmarks
include neutrophil accumulation, alveolar epithelial and endothelial cell injury, and loss of epithelial-capillary
integrity. For alveolar repair to occur, inflammation must be halted, debris and inflammatory cells removed,
injured tissue cells replaced, and capillary barrier function re-established. Macrophages are key players in all of
these. The primary objective of this proposal is to create a Program in Lung Macrophage Biology that will
determine how lung macrophages are programmed to halt inflammation and promote alveolar repair.
A concept at the heart of the proposal is that of macrophage subsets. During health, the airspaces are
occupied by a stable population of resident alveolar macrophages (RAM) that arise during embryogenesis and
self-renew throughout life. RAMs remain during inflammation but are joined by recruited macrophages (RecM)
that mature from circulating monocytes. These RecM remain in the lungs until alveolar function is restored, and
then in most cases undergo apoptosis. However, in certain situations RecM escape apoptosis. We have shown
that this is associated with the development of fibrosis.
The precise roles played by RAMs vs RecM in the resolution of inflammation and promotion of tissue repair
remain largely unknown. However, our data suggest that their respective roles are very different. In this
context, the Program in Lung Macrophage Biology will explore 3 complementary themes. Theme 1 tests the
hypothesis that RecM apoptosis is essential for the resolution of inflammation and that delayed apoptosis leads
to fibrosis. The mechanisms that regulate the extrinsic apoptosis pathway and the intracellular proteins that
block it will be studied. Theme 2 tests the hypothesis that binding of airway-derived mucins to Siglecs (a class
of sialic acid-binding receptors with immunoinhibitory function) expressed on macrophages calibrates
macrophage inflammatory responses. Theme 3 provides a tight link with the other themes and explores how
cellular metabolism regulates macrophage inflammatory and pro-reparative functions and how it regulates
survival of macrophage subsets. In this context, we propose that RecM preferentially use glycolysis as an
energy source, whereas RAMs have increased utilization of the TCA cycle. HIF-1a is stabilized in RecM and is
viewed as a central metabolic regulator. The 3 themes are further linked by their focus on differential functions
of RAM vs RecM, the utilization of fresh human macrophages and shared use of cutting edge technologies.
The Program leverages a multidisciplinary team of highly accomplished investigators, novel transgenic animal
systems that we have developed, and a strong clinical research component. The latter includes whole human
lungs obtained from donors that died with ARDS, bronchoscopy specimens from patients with ARDS, and LPS
exposure studies with healthy hu...

## Key facts

- **NIH application ID:** 10225232
- **Project number:** 3R35HL140039-03S1
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** William Janssen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $556,324
- **Award type:** 3
- **Project period:** 2018-02-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225232

## Citation

> US National Institutes of Health, RePORTER application 10225232, Lung Macrophage Programming in Acute Lung Injury (3R35HL140039-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10225232. Licensed CC0.

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