Preoperative exercise therapy for surgery triggered inflammation

手术前运动疗法引发炎症

• 批准号: 10684527
• 负责人: Hai Huang
• 金额: $ 36.01万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684527
• 关键词: Abdomen; Adoptive Transfer; Animals; Anti-Inflammatory Agents; Attenuated; Cardiovascular system; Cells; Characteristics; Cytometry; Data; Development; Environment; Enzyme-Linked Immunosorbent Assay; Excision; Exercise; Exercise Therapy; Exhibits; Flow Cytometry; Foundations; Functional disorder; Genetic; Goals; Hepatic; Human; Immune; Immunity; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knowledge; Kupffer Cells; Lead; Lipopolysaccharides; Liver; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Musculoskeletal Diseases; Neutrophil Infiltration; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Pharmacology; Phenotype; Play; Postoperative Complications; Postoperative Period; Process; Randomized Controlled Trials; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; STAT3 gene; Secondary to; Serum; Signal Transduction; Sodium Chloride; Stat3 Signaling Pathway; Testing; Therapeutic; Training; Transaminases; base; cell type; chemokine; cost; cytokine; design; exercise intervention; exercise intolerance; extracellular; immune function; improved; improved outcome; inflammatory milieu; inhibitor; innate immune function; liver injury; liver ischemia; liver transplantation; macrophage; mortality; mouse model; neutrophil; novel; novel strategies; organ injury; prevent; response; single cell technology; single-cell RNA sequencing; surgery outcome; systemic inflammatory response; transcriptomics; tumor-immune system interactions

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.

项目摘要 肝缺血再灌注（I/R）是肝切除术后不可避免的结果， 肝移植导致肝脏手术后显著的发病率、死亡率和成本。但此前的 保护肝脏免受I/R损伤的策略集中于一种特定的已知损伤机制， 其他有害过程。术前/术后锻炼有助于大腹部手术后的恢复 手术众所周知，运动通过调节多个细胞因子， 机制，包括先天免疫细胞的数量和功能的改变，以提供抗- 炎症环境。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）和细胞因子表达， 趋化因子（炎症反应）在肝脏I/R。我们的单细胞RNA测序（scRNA-seq）数据 显示PET改变了常驻Kupffer细胞（KCs）的转录组学特征，使其具有抗炎作用。 profile. PET还促进枯否细胞中的抗炎训练免疫，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，我们发现PET显著减少了中性粒细胞的数量， 中性粒细胞胞外陷阱（NETs）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通过改变训练的免疫力来预防肝脏I/R损伤。 在枯否细胞中，以及NET诱导的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的假设。在目标1中，我们将确定PET保护的机制。 通过将枯否细胞训练为抗炎表型，使肝脏免受I/R损伤。我们将测试 PET通过调节IL-33/ST 2/STAT 3在KC中诱导抗炎训练免疫的假设 信号通路和衣康酸/IRG 1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I/R期间局部和全身损伤。我们 将检验PET通过抑制肝脏I/R后的炎症反应来改善全身炎症损伤的假设。 中性粒细胞募集和NET的形成。我们的建议将描绘PET在 肝脏免疫微环境的调节及肝脏I/R时的全身免疫。的机制 在这些研究中发现的，不仅将为优化这种非药理学基础的 针对手术引起器官损伤的策略，同时也设计了模拟运动的药理学策略 运动不耐受的手术患者。