# Developing and testing novel therapies for the alcoholic lung: our clinical trials pipeline

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $304,638

## Abstract

Since its inception, the primary goal of the Emory Alcohol and Lung Biology Center has been to 
develop novel and effective treatments that can mitigate or even reverse the pathophysiological 
effects of alcohol on the lung. The first two funding cycles were dedicated to elucidating the 
fundamental mechanisms that induce the ‘alcoholic lung phenotype’. Our experimental findings have 
elucidated central roles for oxidative stress (including profound glutathione depletion), zinc 
deficiency, and decreased expression and function of PPARγ in mediating the effects of alcohol. 
More recently we identified that alcohol inhibits the actions of Nrf2, the transcription factor 
that activates the anti-oxidant response element (ARE) and programmatically induces the expression 
of hundreds of genes (including those involved in glutathione homeostasis) required to defend 
against inflammatory stresses. Moreover, Nrf2 and PPARγ activity appear to be zinc-dependent and 
therefore these pathways may be interdependent and therefore coordinately targeted by alcohol. 
Remarkably, these same pathways are targeted during chronic HIV infection, and we have determined 
that alcohol and HIV- related proteins have additive toxicities on lung epithelial and macrophage 
function. As our Center   investigators are also engaged in translational clinical trials in 
HIV-mediated lung disease, we have the unique capacity to study the combined effects of alcohol and 
HIV and how this combination may pose a challenge to developing effective therapies. These 
discoveries have not only revealed the mechanisms by which alcohol renders the lung susceptible to 
injury but have also identified candidate therapies targets that Center investigators are testing 
in experimental models and clinical trials. This new Project 3 will coordinate and direct our 
‘clinical trials pipeline’ and shepherd discoveries from the laboratory to interventional trials. 
The goals of Project 3 are to: 1) Determine the efficacy of dietary supplementation with zinc 
and/or SAMe in reversing the alcoholic lung phenotype in subjects with alcohol use disorders and, 
in parallel, how regular alcohol use affects the efficacy of dietary zinc + SAMe in reversing lung 
dysfunction in individuals living with HIV.  2) Exploit our experimental and clinical translational 
studies on alcohol-induced inhibition of PPARγ signaling to conduct a clinical trial to determine 
if treatment with the PPARγ ligand pioglitazone can reverse the alcoholic lung phenotype in 
subjects with alcohol use disorders. 3) In collaboration with Projects 1 and 2, determine if Nrf2 
activators, alone or in combination with zinc, can rapidly reverse the alcoholic lung phenotype in 
animal models in vivo and in human alveolar macrophages ex vivo, and translate these studies to a 
clinical trial of agents such as sulforaphane, alone or in combination with zinc, in subjects with 
alcohol use disorders. Success in any of these trials in our pipeline ...

## Key facts

- **NIH application ID:** 9996436
- **Project number:** 5R01AA025857-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** David Marshall Guidot
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $304,638
- **Award type:** 5
- **Project period:** 2016-09-25 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996436

## Citation

> US National Institutes of Health, RePORTER application 9996436, Developing and testing novel therapies for the alcoholic lung: our clinical trials pipeline (5R01AA025857-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996436. Licensed CC0.

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