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.
Preoperative exercise therapy (PET) is a highly applicable non-pharmacological-based therapy and has successfully reduced postoperative complications and conferred better recovery from major liver surgery. This project will determine the mechanisms by which PET prevents liver ischemia/reperfusion injury which is an unavoidable consequence of major liver surgery by altering the trained immunity in hepatic resident macrophages (Kupffer cells), and the NET-induced local and systemic inflammatory response. The finding from this proposal will provide the knowledge foundation for not only optimizing the development of PET against surgery-induced organ injury but also devising exercise-mimicking pharmacological strategies for patients who are exercise intolerant.
