# Interactions between neutrophils and cholangiocytes in alcoholic hepatitis

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $620,810

## Abstract

PROJECT SUMMARY/ABSTRACT
Alcoholic hepatitis is a serious and potentially life-threatening complication of alcoholic liver disease, with a
short-term mortality as high as 20-50%. Traditionally, alcoholic hepatitis is thought to result mostly from
hepatocellular damage. However, recent evidence suggests that alcoholic hepatitis also results in cholestatic
liver injury, and that worsening cholestasis in fact is associated with a worse prognosis. This is an important
concept because cholestasis generally is a separate process from hepatocellular injury, and so its presence
may suggest previously unappreciated pathogenic mechanisms and potential therapeutic targets. Cholestasis
may reflect impaired secretory function of hepatocytes, but often instead reflects impaired secretion by bile
duct epithelial cells, or cholangiocytes. A variety of liver diseases are largely or entirely due to cholangiocyte
damage or dysfunction, and these cholangiopathies are characterized by cholestasis. Despite their widely
different etiologies, loss of expression of type 3 inositol trisphosphate receptors (ITPR3) from cholangiocytes is
a final common pathway among the cholangiopathies that results in cholestasis. ITPR3 plays this important
role because it is the primary intracellular calcium release channel in cholangiocytes, and its expression is
necessary to mediate biliary fluid and bicarbonate secretion. This project will investigate the idea that
cholangiocytes are involved in the cholestasis that occurs in alcoholic hepatitis and that, as in other
cholangiopathies, this also is due to loss of ITPR3. In particular, this project will test the hypothesis that the
cholestatic changes that occur in alcoholic hepatitis are due in part to direct interactions between
cholangiocytes and neutrophils. Moreover, the relative contribution of cholangiocytes and hepatocytes to
cholestasis will be determined. This will be tested through three specific aims: (1) We will determine whether
and why the neutrophils in alcoholic hepatitis behave abnormally towards cholangiocytes; (2) We will
determine whether and why the cholangiocytes in alcoholic hepatitis have intrinsic secretory defects; and (3)
We will identify targets for therapy based on the mechanism(s) of neutrophil-cholangiocyte interactions. This
project has the potential to fundamentally shift our understanding of alcoholic hepatitis, by establishing a new
role for cholangiocytes in this disease and by determining how neutrophils interact with them to cause
cholestasis. Such a paradigm shift in our understanding of the molecular pathogenesis of this disorder may in
turn define new targets for therapy. Considering that no new therapy for alcoholic hepatitis has been shown to
be efficacious since the use of steroids was introduced 40 years ago, this work has the potential to
fundamentally alter the approach to patients with this life-threatening illness.

## Key facts

- **NIH application ID:** 10878956
- **Project number:** 5R01AA028765-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** MICHAEL H NATHANSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $620,810
- **Award type:** 5
- **Project period:** 2021-09-25 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878956

## Citation

> US National Institutes of Health, RePORTER application 10878956, Interactions between neutrophils and cholangiocytes in alcoholic hepatitis (5R01AA028765-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10878956. Licensed CC0.

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