# Inflammation Resolution in Liver Ischemia-Reperfusion Injury

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $390,000

## Abstract

Project Summary:
 Ischemia reperfusion injury (IRI) is the major risk factor in liver tumor resection and transplantation. Innate
immune activation drives the development of tissue injury via interactions of danger associated molecular
pattern (DAMP) and pattern recognition receptors. As an integral part of the disease process, inflammation
resolution in liver IRI has not been well defined. Questions of whether and how IRI may lead to transplant
rejection remain to be answered. Inflammation resolution is an active process, initiated by or overlapped with
immune activation. Thus, anti-inflammatory strategy by itself may potentially interfere with inflammation
resolution. The pro-resolution strategy is, therefore, is critical for the true restoration of tissue homeostasis.
 Preliminary experiments have been performed to define inflammation resolution in a murine liver partial
warm ischemia model with data on the kinetic changes in histopathology, inflammatory gene expressions and
macrophages (MФs). KCs are the dominant player in the liver inflammation resolution. Their depletion by
clodronate-liposomes (CL) results in significant delays in the resolution of liver IRI (14 days) with increased
expressions of pro-inflammatory and fibrosis genes, as compared with the depletion of CD11b+iMФ (in CD11b-
DTR mice). The KC reconstitution in these CL-treated mice restored the resolution kinetics. Experiments with
TAM RTK deficient mice and TIM-4 depleting Abs showed that both Mer receptor tyrosine kinase (RTK) and
TIM-4 are critical for the KC function in the resolution of liver IRI.
 The current project will take advantage of novel mouse genetic tools to elucidate KC-specific function in
liver IRI in both partial warm ischemia, as well as liver transplantation models. Experiments are designed to
test the hypothesis that embryonic KCs are the most effective reparative MФs in the resolution of liver IRI in
MerTK/TIM-4 dependent manner via Liver X Receptor (LXR) - and lipoxygenase (LOX) -mediated effector
pathways. Enhancement of pro-resolution function of KCs protects liver Tx and inhibits alloimmune activation.
 Aim 1 will determine the functional mechanism of KCs in the resolution of liver IRI. Aim 2 will define
MerTK-mediated pro-resolution effector pathways in KCs. Aim 3 will determine roles of KCs in liver
transplantation. Results of the study will help to delineate the inflammation resolution mechanism in liver IRI
and identify novel pro-resolving therapeutic targets for future clinical application.

## Key facts

- **NIH application ID:** 10328214
- **Project number:** 2P01AI120944-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** YUAN ZHAI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,000
- **Award type:** 2
- **Project period:** 2017-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328214

## Citation

> US National Institutes of Health, RePORTER application 10328214, Inflammation Resolution in Liver Ischemia-Reperfusion Injury (2P01AI120944-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10328214. Licensed CC0.

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