# Integrated mechanisms of primary and chronic graft dysfunction following lung transplantation

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2024 · $2,803,961

## Abstract

Lung transplantation is increasingly used to treat an expanding list of end-stage lung diseases, resulting in an
over >50% increase in the number of lung transplant procedures in the US in the last decade. Unfortunately,
survival following lung transplant is the worst amongst solid organs with only 80% and 50% of patients alive at 1
and 5 years, respectively. Primary graft dysfunction (PGD) affects over 50% of recipients within 24 hours of
transplantation and has emerged as the most important risk factor for both short-term mortality and long-term
graft loss from chronic lung allograft dysfunction (CLAD). The investigators in this PPG have made important
contributions to a growing molecular understanding of the complex interplay between immune and lung
parenchymal cells that underlie PGD and CLAD. In Project 1, we dissect molecular mechanisms underlying our
discovery that lung restricted alloantibodies (LRA), present in over 30% of lung transplant recipients, are
associated with PGD. In Project 2, we dissect physiologic and molecular mechanisms underlying prevalent
abnormalities in esophageal function that lead to acid aspiration and worsen CLAD severity. In Project 3, we will
credential profibrotic MoAMs as causal drivers of lung fibrosis in murine models and in patients with CLAD. In
Project 4, ESI, we test whether mitochondrial dysfunction in the alveolar epithelium predisposes lung transplant
recipients to pathologic activation of the integrated stress response (ISR) that precludes lung repair. Together
our published and preliminary data support our overarching hypothesis that acute neutrophil-mediated lung injury
mechanisms such as PGD and acid aspiration drive CLAD progression by promoting the development of LRA,
recruiting profibrotic MoAM, and inducing epithelial cell mitochondrial damage causing an ISR-mediated barrier
to epithelial repair. We will test this hypothesis in 4 interrelated and synergistic projects.
Project 1. To determine whether LRA interact with donor derived NCM and recipient CM to worsen PGD
via the activation of complement dependent and independent pathways.
Project 2. To determine whether physiologic abnormalities in the esophagus after lung transplant cause
gastric aspiration that induces LRA and CLAD progression via neutrophils and MoAM.
Project 3. To determine whether CSF1 drives the recruitment and retention of profibrotic MoAM and
whether their detection in bronchoalveolar lavage fluid can serve as a biomarker for CLAD.
Project 4. To determine whether mitochondrial dysfunction in the airway and alveolar epithelium results
in pathologic activation of the ISR that precludes normal epithelial repair to promote CLAD.
The Human and Clinical Phenotyping Core (Core B), Mouse and Cell Phenotyping Core (Core C) and
Administrative Core (Core A) will support these synergistic projects using murine models and clinical and
molecular data collected from lung transplant recipients to identify actionable pathways that can be
the...

## Key facts

- **NIH application ID:** 10933919
- **Project number:** 1P01HL169188-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Ankit Bharat
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,803,961
- **Award type:** 1
- **Project period:** 2024-09-17 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933919

## Citation

> US National Institutes of Health, RePORTER application 10933919, Integrated mechanisms of primary and chronic graft dysfunction following lung transplantation (1P01HL169188-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10933919. Licensed CC0.

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