Preoperative exercise therapy for surgery triggered inflammation

项目总结 肝脏缺血再灌注(I/R)是大范围肝切除和肝脏切除后不可避免的后果 导致肝脏手术后显著的发病率、死亡率和费用的移植。但是，以前的 保护肝脏免受I/R损伤的策略主要集中在一种特定的已知损伤机制上， 完好无损的其他有害过程。术前/术后锻炼促进腹部大出血后的康复 做手术。众所周知，运动通过调节多个因素对手术结果产生有益影响。 机制包括改变先天免疫细胞的数量和功能，以提供一种抗 炎性环境。我们新的初步数据表明，术前运动疗法(PET) 显著降低血清转氨酶水平(肝损伤)和细胞因子及 肝脏I/R期间的趋化因子(炎症反应)我们的单细胞RNA测序(scRNA-seq)数据 发现PET改变了常驻Kupffer细胞(KCs)的转录特征，使其具有抗炎作用 侧写。PET还可促进库普弗细胞的抗炎训练免疫，这与 循环损伤相关分子模式(DAMP)IL-33和衣康酸代谢增加 重新编程。此外，我们还表明，PET显著减少了中性粒细胞的数量，并 中性粒细胞胞外陷阱(Net)的形成是肝脏I/R后局部和全身损伤的关键介质。 鉴于这些发现，我们假设PET通过改变训练性免疫来预防肝脏I/R损伤 在Kupffer细胞中，Net诱导局部和全身炎症反应。我们将测试我们的 通过追求两个具体目标来进行假设。在目标1中，我们将确定PET保护的机制 通过将Kupffer细胞培养成抗炎表型，使肝脏免受I/R损伤。我们将测试 PET通过调节IL-33/ST2/STAT3诱导KCs抗炎训练性免疫的假说 信号通路和衣康酸/IRG1代谢重编程通路。在目标2中，我们将定义 PET通过减少中性粒细胞胞外陷阱减轻肝脏I/R时的局部和全身损伤。我们 将检验PET可通过抑制肝I/R后全身炎症损伤来改善肝脏I/R后全身炎症损伤的假说 中性粒细胞募集和网状结构的形成。我们的建议将描绘出PET的分子机制 肝脏I/R过程中肝脏免疫微环境和系统免疫的调节机制 在这些研究中的发现将不仅为优化这种基于非药理学的 对抗手术所致器官损伤的策略，但也要设计类似运动的药理学策略 适用于运动不耐受的外科手术患者。

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.