# NIH grant: Chronic Alcohol Consumption Dysregulates Lung Hyaluronic Acid (1R01AA032629-01A1) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R01AA032629-01A1)

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NIH grant 1R01AA032629-01A1: Chronic Alcohol Consumption Dysregulates Lung Hyaluronic Acid
Institute: {'code': 'AA', 'abbreviation': 'NIAAA', 'name': 'National Institute on Alcohol Abuse and Alcoholism', 'admin_org_id': '12500001', 'admin_funding_url': ''}. PI: Samantha M. Yeligar. Award: $418923.
Start: 2026-09-05T00:00:00.
PROJECT SUMMARY/ABSTRACT:
 Alcohol use disorder (AUD), which affects over 26 million people aged 21 years+ in the US, increases
the risk for pneumonia by 2-4-fold, resulting in high healthcare costs due to comorbidities and hospitalizations.
Lung macrophages are critical for innate immune defense against inhaled pathogens by engulfing and killing
them. Chronic ethanol (EtOH) consumption impairs phagocytosis in lung macrophages, but our prior work and
preliminary data indicate there is heterogeneity in lung macrophages’ immune response to bacterial infections.
In response to insults, subpopulations of macrophages are recruited into the lung as interstitial macrophages
(IMs), monocyte-derived alveolar macrophages (MoAMs), and tissue-resident alveolar macrophages (RAMs).
Understanding how phagocytosis is suppressed in macrophage populations specifically dysregulated by EtOH
is critical to being able to develop targeted therapies to decrease susceptibility to pneumonia in people with
AUD. The primary objective of this project seeks to address this critical knowledge gap by determining the
impact of EtOH-induced reactive oxygen species (ROS) production on the composition of IMs, MoAMs, and
RAMs in the alveolus plus their immune phenotype at baseline and in response to a bacterial infection.
Hyaluronic acid (HA) is an extracellular matrix polysaccharide whose signaling directs inflammation in
numerous lung diseases. Low molecular weight HA signaling is pro-inflammatory, while high molecular weight
HA signaling is anti-inflammatory. ROS perturbs HA molecular dynamics, which could alter mitochondrial
bioenergetics where ATP generated from mitochondria is key for phagocytosis. Our work shows that chronic
alcohol consumption increases ROS in the lungs and promotes anti-inflammatory and metabolically
dysregulated phenotypes in lung macrophages. We hypothesize that chronic EtOH consumption increases
ROS in the bronchoalveolar lavage fluid (BALF) and differentially alters HA synthesis and fragmentation in IMs,
MoAMs, and RAMs which leads to alternative/deactivated and dysregulated metabolic phenotypes that impair
phagocytosis. Preliminary studies also show that treatment with pioglitazone (PIO), an agent with antioxidant
effects, restores lung redox balance in EtOH-fed mice and decreases HA content in the lungs of AUD
individuals. We postulate that PIO treatment will restore redox balance; thereby, reversing EtOH-induced
alterations in HA dynamics in dysfunctional lung macrophages and improving their phagocytic abillity. Using a
scientifically rigorous approach, state-of-the-art techniques, translational models, and samples from people
with AUD, we will (1) define how chronic EtOH consumption affects alterations in HA, activation state,
metabolic phenotype, and immune phenotype of lung macrophage subpopulations and (2) determine how
EtOH-induced lung redox imbalance dysregulates HA dynamics in lung macrophage subpopulations. These
studies can aid in specifically targeting treatments to dysfunctional macrophages and improve lung immunity in
people with AUD while also providing valuable insights into HA derangements in other pulmonary diseases.
```



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