# Mechanisms of neutrophil extracellular trap formation and contribution to biliary fibrosis in biliary atresia

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $545,972

## Abstract

PROJECT SUMMARY/ABSTRACT
Biliary atresia (BA) is an inflammatory, sclerosing lesion of the biliary tree that presents in infancy and is
associated with significant biliary fibrosis. The degree of fibrosis at presentation is unprecedented compared to
any other organ-specific disease of infancy and the vast majority of BA patients will need liver transplantation
for survival. Various immune pathways have been implicated in cholangiocyte injury in BA, yet key immune
pathways that promote fibrosis are unknown. A critical barrier to discovering novel therapies in BA is the lack of
an understanding of key cellular mechanisms promoting biliary fibrosis. The biomarker CXCL8 (IL-8), a
neutrophil chemoattractant and activator, and neutrophil extracellular traps (NETs) have been previously
shown to predict worse outcomes in BA. Significant preliminary data within this proposal reveals that
neutrophils are chronically activated in BA patients, with persistent CXCL8-CXCR2-mediated NET formation
(NETosis). Constituents of BA NETs include pro-fibrogenic proteins and NETs positively correlate with
biomarkers of injury and fibrosis. The hypothesis to be tested is that the immunopathogenesis of BA involves
CXCL8-CXCR2-mediated NETosis, resulting in NET-induced portal fibroblast and stellate cell activation. The
rotavirus-induced mouse model of BA (murine BA), as well as analyses of human biospecimens, will be
employed to address the hypothesis. Specific Aim 1 will determine if neutrophil CXCR2 activation is essential
for NETosis in murine BA. Specific Aim 2 will determine the predominant source of reactive oxygen species
that is necessary for NETosis (NADPH-oxidase dependent versus mitochondrial source). Specific Aim 3 will
establish the pro-fibrogenic role of NETs in BA, including portal fibroblast and hepatic stellate cell activation
through use of primary cell lines and hepatic organoids. Impact. Discoveries from this research could be highly
impactful, with increased knowledge gained in neutrophil biology and with the identification of novel
therapeutics targeting NETosis that would prevent biliary cirrhosis in children with BA.

## Key facts

- **NIH application ID:** 10938525
- **Project number:** 1R01DK140072-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Michael B Dwinell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $545,972
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938525

## Citation

> US National Institutes of Health, RePORTER application 10938525, Mechanisms of neutrophil extracellular trap formation and contribution to biliary fibrosis in biliary atresia (1R01DK140072-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10938525. Licensed CC0.

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