# Mechanisms of Alcohol-Induced Lung and Liver Injury

> **NIH NIH P50** · UNIVERSITY OF LOUISVILLE · 2020 · $172,858

## Abstract

Chronic ethanol abuse leads to increased susceptibility to acute lung injury (ALI) and mortality in the setting 
of sepsis. We believe that this is due, in part, to alterations in the expression of tissue remodeling genes that 
prime the lung to disrepair after injury. This is supported by our own findings showing that lungs harvested 
from rodents treated with ethanol show increased expression of fibronectin, matrix metalloproteinases, and 
transforming growth factor β; we also demonstrated activation of matrix remodeling in alcoholics. Together 
with changes in oxidative stress and epithelial cell dysfunction, these alterations represent key features of what 
has been termed the “alcoholic lung phenotype”. Despite the above advances, we still do not understand the 
mechanisms that lead to these changes nor the role of matrix remodeling in the alcoholic lung. Importantly, the 
mechanisms by which these changes render the lung susceptible to disrepair after injury remain unclear. We 
hypothesize that chronic ethanol promotes redox stress that triggers extracellular matrix (ECM) remodeling 
resulting in the `re-pavement' of the lung with a `pro-inflammatory' ECM characterized by increased expression 
of fibronectin EDA and collagen V, two molecules implicated in tissue disrepair. Upon injury of the alcoholic 
lung, epithelial cells trying to populate denuded areas become exposed to this “aberrant” ECM resulting in 
increased permeability, while incoming immune cells exposed to this ECM experience exaggerated activation. 
Together, these processes enhance inflammation and epithelial cell dysfunction leading to disrepair and, 
ultimately, ALI. We have observed similar derangements in the aging lung and speculate that ethanol-induced 
redox stress promotes accelerated aging of the lung through epigenetic modifications that drive ECM 
remodeling. Our hypothesis is supported by several in vivo studies demonstrating a role for the ECM in the 
lung's response to injury. Second, we showed that primary lung cells harvested from ethanol-treated animals 
deposit a pro-inflammatory matrix. Third, we found that alveolar epithelial cells cultured on different matrices 
show alterations in their expression of claudins resulting in barrier dysfunction. Fourth, like ethanol, we found 
that aging also promotes ECM remodeling and this defect is associated with epigenetic histone modifications 
that drive fibronectin gene expression; we speculate that similar mechanisms are taking place here. Finally, 
recent studies in our laboratory suggest that the above effects might be dependent on ethanol-induced redox 
stress and could potentially be ameliorated by dietary interventions targeting redox stress. We aim to test the 
hypothesis in specific aims designed to: 1) Examine the effects of ethanol-induced ECM remodeling on 
immune cells and epithelial cells in vitro and explore its role in susceptibility to ALI in vivo; 2) Examine ethanol- 
dependent, gene-specific, prom...

## Key facts

- **NIH application ID:** 9917672
- **Project number:** 5P50AA024337-05
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** JESSE ROMAN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $172,858
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917672

## Citation

> US National Institutes of Health, RePORTER application 9917672, Mechanisms of Alcohol-Induced Lung and Liver Injury (5P50AA024337-05). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9917672. Licensed CC0.

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