# Preoperative exercise therapy for surgery triggered inflammation

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $335,400

## Abstract

PROJECT SUMMARY
 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. However, previous
strategies to protect the liver from I/R injury have focused on one specific known injury mechanisms, leaving
intact other detrimental processes. Pre/post-operative exercise facilitates recovery after major abdominal
surgery. It is known that exercise confers beneficial effects on the surgical outcome by regulating multiple
mechanisms, including alteration of quantity and function of innate immune cells to provide an anti-
inflammatory environment. Our novel preliminary data indicate that preoperative exercise therapy (PET)
significantly reduced serum aminotransferase levels (liver damage) and expression of cytokines and
chemokines (inflammatory responses) during liver I/R. Our single-cell RNA-sequencing (scRNA-seq) data
revealed PET altered the transcriptomic profile of resident Kupffer cells (KCs) towards an anti-inflammatory
profile. PET also promoted the anti-inflammatory trained immunity in Kupffer cells which is associated with
increased circulating damage-associated molecular pattern (DAMP) IL-33 and itaconate metabolic
reprogramming. Furthermore, we show that PET significantly decreased the number of neutrophils and
formation of neutrophil extracellular traps (NETs), as key mediators of local and systemic injury after liver I/R.
Given these findings, we hypothesize that PET prevents liver I/R injury by altering the trained immunity
in Kupffer cells, and the NET-induced local and systemic inflammatory response. We will test our
hypothesis by pursuing two specific aims. In Aim 1, we will determine the mechanism by which PET protects
the liver from I/R injury via training Kupffer cells towards an anti-inflammatory phenotype. We will test the
hypothesis that PET induces an anti-inflammatory trained immunity in KCs via modulation of IL-33/ST2/STAT3
signaling pathway and itaconate/IRG1 metabolic reprogramming pathway. In Aim 2, we will define the role of
PET in attenuating local and systemic injury during liver I/R via reduction of neutrophil extracellular traps. We
will test the hypothesis that PET ameliorates systemic inflammatory injury after liver I/R through suppression of
neutrophil recruitment and formation of NETs. Our proposal will delineate the molecular mechanisms of PET in
the regulation of hepatic immune microenvironment, and systemic immunity during liver I/R. The mechanisms
discovered in these studies will provide the foundation for not only optimizing this non-pharmacological-based
strategy against surgery-induced organ injury but also devising exercise-mimicking pharmacological strategies
for patients undergoing surgery who are exercise intolerant.

## Key facts

- **NIH application ID:** 10263293
- **Project number:** 5R01GM137203-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Hai Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,400
- **Award type:** 5
- **Project period:** 2020-09-18 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263293

## Citation

> US National Institutes of Health, RePORTER application 10263293, Preoperative exercise therapy for surgery triggered inflammation (5R01GM137203-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10263293. Licensed CC0.

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