# Preoperative exercise therapy triggers trained immunity in KCs via cholinergic anti-inflammatory pathway

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2024 · $215,000

## Abstract

PROJECT DESCRIPTION: The goal of this Administrative Supplement application is to support the purchase
of a multi-lane metabolic & telemetric treadmill from Columbus Instruments. This equipment is essential for
determining how preoperative exercise therapy (PET) modulates anti-inflammatory trained immunity in Kupffer
cells (KCs) via hepatic vagal neurotransmitter, Acetylcholine. This study is highly relevant to the parent grant
(R01GM137203) entitled "Preoperative exercise therapy for surgery triggered inflammation". Liver ischemia
and reperfusion (I/R) is an unavoidable consequence of major liver resection and liver transplantation that
leads to significant morbidity, mortality, and costs after liver surgery. Previous strategies to protect the liver
from I/R injury have typically focused on specific known injury mechanisms, often leaving other detrimental
processes unaddressed. Pre/post-operative exercise facilitates recovery after major abdominal surgery. It has
beneficial effects on the surgical outcome by regulating multiple mechanisms, including the quantity and
function of innate immune cells to confer an anti-inflammatory environment. We have discovered that PET
significantly reduced liver damage and inflammatory responses after liver I/R via metabolic reprogramming
Kupffer cells with anti-inflammatory trained immunity. However, the precise mechanisms by which PET triggers
metabolic changes in KCs remains unclear. Our recent preliminary data that PET increased levels of
acetylcholine in the liver and blocking α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) abrogated
the long-lasting protective effect of PET on liver I/R injury. Therefore, we hypothesize that PET triggers an anti-
inflammatory trained immunity in KC against liver I/R injury via cholinergic anti-inflammatory pathway (CAIP).
The multi-lane metabolic & telemetric treadmill is a state-of-the-art system designed for enhanced accuracy
and efficiency in metabolic and physiological monitoring during small animal exercise. Our proposed vagal tone
studies with metabolic treadmill will significantly expand the scope of the parent R01 award by addressing two
new questions related to those already being investigated in the parent R01 award: 1) Does PET trigger
trained immunity in KC to protect liver from I/R injury via hepatic vagus nerve? 2) Does PET metabolically-
epigenetically reprogram KCs via a7nAChR to trigger trained immunity? In summary, the multi-lane metabolic
& telemetric treadmill will significantly enhance our understanding of the effects of PET on modulating
immunometabolism in hepatic immune cells against liver I/R injury and drives significant scientific
advancements in the field of immunometabolism.

## Key facts

- **NIH application ID:** 11100211
- **Project number:** 3R01GM137203-05S1
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Hai Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $215,000
- **Award type:** 3
- **Project period:** 2022-08-16 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100211

## Citation

> US National Institutes of Health, RePORTER application 11100211, Preoperative exercise therapy triggers trained immunity in KCs via cholinergic anti-inflammatory pathway (3R01GM137203-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11100211. Licensed CC0.

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