# Inducible epithelial resilience during pneumonia

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $412,500

## Abstract

Abstract
Pneumonia is a leading cause of morbidity and mortality across the socioeconomic spectrum. It is also the
most frequent cause of acute respiratory distress syndrome (ARDS), due in large part to a harmful imbalance
of biological pathways promoting antimicrobial resistance and tissue resilience. The latter is essential for
maintaining barrier integrity and limiting alveolar flooding, but host mechanisms protecting the delicate air-liquid
interface during pneumonia remain poorly understood. We have previously shown that the IL-6 family cytokine
leukemia inhibitory factor (LIF) is critical for limiting acute lung injury in response to infection, and its protective
properties do not appear to influence host immunity. A more complete understanding of the biological signals
up- and downstream of this cytoprotective factor, which are currently unclear, may provide a unique and
important window into pathways that dictate tissue homeostasis without compromising antimicrobial defense.
Our published and preliminary results suggest that lung epithelium is both the source and target of LIF during
pneumonia, serving as a mechanism of inducible resilience. Initial results also suggest that this response is
macrophage-mediated, and that it may involve LIF-dependent changes in the cytoprotective transcriptional co-
activator Yes-associated protein (YAP), as well as regulation of the low-density lipoprotein receptor-1 (LOX-1),
which can promote injury and cell death. Here we propose the central hypothesis that epithelial integrity is
maintained in pneumonic lungs by a macrophage-dependent paracrine LIF axis that promotes tissue
resilience. This hypothesis will be tested by pursuing the following 3 aims: Aim 1) Test the hypothesis that
LIFRβ signaling in lung epithelium prevents acute lung injury during pneumonia; Aim 2) Test the hypothesis
that macrophage-epithelial communication initiates the tissue protective circuit mediated by LIF; and Aim 3)
Test the hypothesis that LOX-1 induction sensitizes epithelial cells to pneumonic lung injury, and is countered
by LIF to fortify tissue resilience. Studies designed to address these aims will employ complementary in vivo
and ex vivo strategies to reveal novel pathways of tissue protection in the setting of lung infection. We
anticipate that these findings will be leveraged for the development of novel clinical interventions in patients
with or at risk for pneumonia and ARDS.

## Key facts

- **NIH application ID:** 9962448
- **Project number:** 5R01HL111449-09
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Lee Quinton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,500
- **Award type:** 5
- **Project period:** 2012-08-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962448

## Citation

> US National Institutes of Health, RePORTER application 9962448, Inducible epithelial resilience during pneumonia (5R01HL111449-09). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9962448. Licensed CC0.

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