# Causes of Lung Barrier Dysfunction in a Translational Model of Chronic Alcohol Ingestion

> **NIH NIH F31** · EMORY UNIVERSITY · 2020 · $45,520

## Abstract

SUMMARY
Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung disease due to significant
airspace (alveolar) flooding, also known as pulmonary edema. Chronic alcohol abuse significantly increases the
severity and risk of developing ARDS. In the normal lung, sodium-driven fluid clearance and epithelial barrier
integrity maintain the airspace fluid balance. The alveoli, where gas exchange occurs, is surrounded by a fluid-
filled interstitium and capillaries. In response to chronic alcohol use, fluid in the airspace increases due to
paracellular leak from the interstitium and capillary blood vessels, rendering the lung more susceptible to
developing ARDS. Patients with a history of chronic alcohol abuse resolve increased extravascular lung fluid
slower. Alcohol abuse is also a significant risk factor for critical illnesses, such as pneumonia, that require
rehydration or blood pressure stabilization, treatments that increase pressure from fluid in the interstitium
surrounding the alveoli. I will first use a novel approach to measure fluid pressure-induced leak in the alcoholic
lung and define the mechanisms that cause differential permeability by measuring the effect of increased fluid
pressure on pulmonary edema in alcoholic lung syndrome at baseline and in pneumonia. To accomplish this, I
will measure the threshold at which alveolar flooding occurs in normal and alcohol-fed mice at baseline and in
response to bacterial pneumonia; at the same intravascular injection volume, we hypothesize that lungs from
alcohol-fed mice are more susceptible to alveolar flooding than a healthy lung. Identifying a lowered leak
threshold could impact the clinical management of patients with a history of alcohol abuse. In addition to leak
threshold, the molecular mechanisms behind alcoholic lung syndrome need to be further investigated. Tight
junction (TJ) proteins regulate paracellular solute passage and prevent fluid leakage into the airspace. Chronic
alcohol abuse impairs the alveolar epithelial barrier by increasing paracellular diffusion and changing the protein
composition of claudins, a family of TJ proteins that regulate fluid and solute homeostasis. Specifically, alcohol
decreases the barrier-protective TJ protein Claudin-4 and increases the barrier-disruptive TJ protein Claudin-5
in cultured alveolar epithelial cells. In the second aim, I will measure the effect of altered Claudin-4 and/or
Claudin-5 expression on lung permeability in vivo. I will manipulate levels of Claudin-4 and Claudin-5 in the lower
airway and measure changes in baseline lung permeability using a modified Evans Blue permeability assay. In
this project, I hypothesize that chronic alcoholism decreases Claudin-4 and increases Claudin-5 which
impair alveolar epithelial barrier function and increases the sensitivity of the lung to develop alveolar
flooding. A long-term goal for this translational project is to provide a foundation to inform future clinical studies
...

## Key facts

- **NIH application ID:** 10023172
- **Project number:** 5F31HL149323-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Lauren Ann Jeffers
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-08-21 → 2022-08-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023172

## Citation

> US National Institutes of Health, RePORTER application 10023172, Causes of Lung Barrier Dysfunction in a Translational Model of Chronic Alcohol Ingestion (5F31HL149323-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10023172. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*