# Physiologic and molecular mechanisms linking gastroesophageal reflux with chronic lung allograft dysfunction

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2024 · $414,746

## Abstract

The goal of this proposal is to elucidate physiologic mechanisms that promote gastric aspiration in lung transplant
recipients and identify molecular mechanisms by which microaspiration worsens PGD and CLAD. GERD is
extremely common in patients with chronic lung disease and lung transplant patients placing them at risk for
microaspiration of stomach contents. While investigators recognize microaspiration as a biologically plausible
contributor to lung transplant outcomes, data causally linking esophageal dysfunction and GERD-associated
microaspiration with graft dysfunction are lacking. Furthermore, whether the lung transplant procedure causes
esophageal dysfunction to promote GERD and CLAD is unknown. Given the prevalence of GERD after lung
transplant (as high as 75% in some series), some investigators recommend the routine use of fundoplication or
universal proton pump inhibitors following lung transplant but that has yielded inconsistent results in ameliorating
CLAD while suffering from attendant risks of therapy. We reason that elucidating the physiologic mechanisms
driving GERD can at a minimum better stratify patients for surgical therapies like fundoplication. Similarly,
understanding the molecular events linking microaspiration with PGD and CLAD can inform the development of
medical therapies to treat aspiration-induced injury to prevent or slow CLAD progression.
Lung restricted autoantibodies (LRA) against lung self-antigens have emerged among the strongest risk factors
for both PGD and CLAD in humans and mice. Multiple studies have shown that over a third of patients undergoing
lung transplantation have pre-existing LRA and up to 60-70% of those that are negative initially develop de novo
LRA within the first two years of transplantation, which is independently associated with increased CLAD risk. In
murine models, LRA drive the pathogenesis of PGD, prevent the development of allotolerance with co-
stimulatory blockade, and abrogate established allotolerance. Using a well-established murine model of CLAD
developed by a multinational team of investigators, we show exciting new data that acid aspiration results in the
de novo development of LRA through recruitment of neutrophils and monocyte derived alveolar macrophages
and by promoting antigen epitope spreading. We suggest direct and immunologic injury to the lung epithelium
in response to acid aspiration induces mitochondrial dysfunction leading to a pathologic activation of the ISR that
precludes epithelial repair. These data support our overarching hypothesis that physiologic dysfunction in the
esophagus and accompanying GERD predisposes to the recruitment of neutrophils and MoAM to the allograft
resulting in the generation of LRA while to worsen CLAD. We will test this using two interrelated aims:
Aim 1: To determine whether acid aspiration recruits neutrophils and monocyte-derived alveolar
macrophages to the graft that induce de novo lung-restricted autoantibodies and worsen CLAD.
A...

## Key facts

- **NIH application ID:** 10933924
- **Project number:** 1P01HL169188-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Harris R Perlman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $414,746
- **Award type:** 1
- **Project period:** 2024-09-17 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933924

## Citation

> US National Institutes of Health, RePORTER application 10933924, Physiologic and molecular mechanisms linking gastroesophageal reflux with chronic lung allograft dysfunction (1P01HL169188-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10933924. Licensed CC0.

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