# Lung transplant injury drives chronic lung allograft dysfunction via recruitment ofmonocyte-derived alveolar macrophages

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $728,331

## Abstract

Project Summary: For many patients with advanced lung disease, lung transplantation remains the only
viable therapeutic option to extend life. Yet the 5-year survival for lung transplant patients is 54%, the worst
among solid organ transplant recipients. Chronic lung allograft dysfunction (CLAD) is the leading cause of
morbidity and late mortality after lung or heart-lung transplantation. Hence, identification of biomarkers and
novel therapeutic targets is essential to prevent or treat CLAD and extend survival after lung transplantation.
While multiple factors contribute to CLAD, early events after the lung transplant procedure play a crucial
role in setting the stage for subsequent CLAD. These include surgical trauma and ischemia-reperfusion
injury that activates circulating and resident immune cells followed by the endothelial injury and immune cell
extravasation. We have reported that monocytes, recruited to the injured lung, can establish a long-term
residency and differentiate into pathogenic monocyte-derived alveolar macrophages. We have causally linked
monocyte-derived alveolar macrophages to tissue-remodeling and fibrosis (resembling CLAD) using a genetic
deletion strategy. Moreover, using unbiased single-cell transcriptomic profiling (RNA-seq) of explanted lung
tissue from the patients with pulmonary fibrosis and biopsies of the donor lung (both obtained during lung
transplantation by lung transplant surgeon – Ankit Bharat, key contributor to this proposal), we identified a
distinct population of pathogenic alveolar macrophages exclusively present in patients with pulmonary fibrosis.
Our computational analyses of single-cell RNA-seq data suggest that monocyte-derived alveolar macrophages
are guided to their new pathogenic niches via plexin D1/signaling and are uniquely maintained by M-CSF/M-
CSFR signaling. Consistent with this hypothesis, targeting M-CSF/M-CSFR signaling specifically eliminated
monocyte-derived alveolar macrophages and ameliorated pathology. We present preliminary data from mouse
models and patients with chronic lung allograft dysfunction supporting relevance of this mechanism for CLAD.
We will thus use mouse models and samples from lung transplant patients to test the hypothesis that
pathogenic monocyte-derived alveolar macrophages, recruited during the initial peri-transplant injury,
establish long term residency via plexin D1/semaphorin signaling and are maintained via M-CSF/M-
CSFR signaling to drive CLAD in three interrelated aims:
Aim 1: To determine whether monocyte-derived alveolar macrophages recruited to the transplanted lung within
day of the transplant are maintained by M-CSF/M-CSFR signaling.
Aim 2: To determine whether pathogenic monocyte-derived alveolar macrophages are localized to regions of
lung fibrosis lung via plexin D1/semaphorin signaling.
Aim 3: To determine whether the emergence of aberrant alveolar macrophages with increased expression of
PLXND1 and autocrine M-CSF/M-CSFR signaling can be ident...

## Key facts

- **NIH application ID:** 10034029
- **Project number:** 1R01HL153312-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Alexander Misharin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $728,331
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10034029

## Citation

> US National Institutes of Health, RePORTER application 10034029, Lung transplant injury drives chronic lung allograft dysfunction via recruitment ofmonocyte-derived alveolar macrophages (1R01HL153312-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10034029. Licensed CC0.

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