AMPK activation and acute lung injury

AMPK 激活与急性肺损伤

• 批准号: 8236661
• 负责人: Jaroslaw Waldemar Zmijewski
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236661
• 关键词: 26S proteasome; 5' -AMP-activated protein kinase; Acute Lung Injury; Affect; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Burn injury; Cells; Cessation of life; Clinical; Endotoxins; Equilibrium; Event; Functional disorder; Generations; Goals; HMGB1 Protein; Hemorrhage; Hydrogen Peroxide; Incidence; Infection; Inflammation Mediators; Inflammatory; Intervention; Laboratories; Lung; Mechanical ventilation; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolic stress; Modeling; Morbidity - disease rate; Mus; Nuclear Translocation; Outcome; Patients; Phosphorylation; Play; Population; Pre-Clinical Model; Process; Production; Property; Reactive Oxygen Species; Regulation; Role; STK11 gene; Sepsis; Severities; Small Interfering RNA; TLR2 gene; TLR4 gene; Tissues; Ubiquitination; cytokine; human FRAP1 protein; improved; knock-down; lung injury; macrophage; mortality; neutrophil; novel therapeutic intervention; prevent; research study; resistin; response

DESCRIPTION (provided by applicant): Acute lung injury (ALI), a pathophysiologic process in which activated neutrophils and macrophages play important roles, is frequently associated with infection, but can also arise from other predisposing events including hemorrhage, burns, or injurious mechanical ventilation. Recent studies from our laboratory and others demonstrate that activation of the AMP-activated protein kinase (AMPK) has potent anti-inflammatory effects in TLR2 or TLR4 stimulated neutrophils, macrophages, and other cell populations relevant to ALI. We have shown that pharmacologic interventions that activate AMPK, even if used after the initiation of TLR4-induced ALI, diminish the severity of lung injury. Although AMPK activation is typically associated with metabolic stress, particularly decrease in intracellular ATP levels or enhanced production of reactive oxygen species (ROS), no increase in AMPK activity has been found in preclinical models of ALI or in patients with sepsis-induced ALI, despite reduction in ATP:AMP ratios or enhanced ROS formation in these settings. The mechanisms that inhibit activation of AMPK in the lungs during ALI are not presently known, but are likely to contribute to the severity of ALI. We hypothesize that AMPK activation has potent anti-inflammatory effects that diminish the severity of ALI and also hypothesize that counter-regulatory mechanisms exist in the TLR2 and TLR4 stimulated neutrophils and macrophages as well as in lungs during ALI that prevent AMPK activation. The specific aims of this project are: 1) To determine the mechanisms through which activation of AMPK decreases the proinflammatory properties of TLR2 and TLR4 stimulated neutrophils and alveolar macrophages and diminishes the severity of lung injury and 2) To determine the mechanisms that inhibit AMPK activation in TLR2 or TLR4 stimulated neutrophils and macrophages and in models of LPS- or sepsis-induced ALI. Our goals are to determine the role of activated AMPK in inhibiting nuclear translocation of NF-?B, by examining the effects of AMPK activation on IKK-dependent phosphorylation of I-?Ba, SCF-¿TrCP mediated ubiquitination of phosphorylated I?Ba and degradation of ubiquitinated I-?Ba by the 26S proteasome. We will also determine the role that activated AMPK plays in regulation of mTORC1 function, particularly mTORC1-dependent production of inflammatory mediators. In addition, the proposed experiments will examine the roles of resistin and HMGB1 in preventing AMPK activation in TLR2 or TLR4 stimulated neutrophils and alveolar macrophages and in the lungs of mice with LPS or sepsis induced ALI. PUBLIC HEALTH RELEVANCE: Acute lung injury is frequently associated with severe infection or blood loss. Although AMP activated protein kinase (also called AMPK) plays a central role in regulating many cellular metabolic pathways, recent study from our and other laboratories have shown that AMPK can diminish activation of inflammatory cells and we have shown that AMPK activation can decrease the severity of endotoxin-induced lung injury. The studies proposed in this application should not only improve understanding of cellular mechanisms of activated AMPK that prevent lung dysfunction and death after hemorrhage and sepsis, but also are likely to suggest novel therapeutic interventions aimed at improving outcome for patients suffering from these clinical problems.

描述（由申请人提供）：急性肺损伤（ALI）是一种病理生理过程，其中活化的中性粒细胞和巨噬细胞发挥重要作用，通常与感染相关，但也可能由其他诱发事件引起，包括出血、烧伤或损伤性机械通气我们实验室和其他实验室的最新研究表明，AMP 激活蛋白激酶 (AMPK) 的激活对 TLR2 或 TLR4 刺激具有有效的抗炎作用。我们已经证明，即使在 TLR4 诱导的 ALI 发生后使用激活 AMPK 的药物干预措施，也能减轻肺损伤的严重程度，尽管 AMPK 激活通常与代谢应激有关。 ，特别是细胞内 ATP 水平降低或活性氧 (ROS) 产生增加，在 ALI 临床前模型或脓毒症诱发的 ALI 患者中，尽管 AMPK 活性降低，但并未发现 AMPK 活性增加。 ALI 期间抑制肺部 AMPK 激活的机制目前尚不清楚，但可能会导致 ALI 的严重程度。减轻 ALI 严重程度的作用，并考虑到 ALI 期间 TLR2 和 TLR4 刺激的中性粒细胞和巨噬细胞以及肺部中存在反调节机制，以防止 AMPK 激活。 1) 确定 AMPK 激活降低 TLR2 和 TLR4 刺激的中性粒细胞和肺泡巨噬细胞的促炎特性并减轻肺损伤严重程度的机制；2) 确定抑制 TLR2 或 TLR4 刺激的中性粒细胞中 AMPK 激活的机制和巨噬细胞以及 LPS 或脓毒症诱导的 ALI 模型中我们的目标是确定激活的 AMPK 在抑制核易位中的作用。 NF-κB，通过检查 AMPK 激活对 IKK 依赖性 I-Ba、SCF-¿ 磷酸化的影响TrCP 介导的磷酸化 I?Ba 的泛素化和 26S 蛋白酶体对泛素化 I?Ba 的降解 我们还将确定激活的 AMPK 在调节 mTORC1 功能中所起的作用，特别是 mTORC1 依赖性炎症介质的产生。拟议的实验将检查抵抗素和 HMGB1 在阻止 TLR2 或 TLR4 刺激的中性粒细胞和肺泡中 AMPK 激活中的作用巨噬细胞和患有 LPS 或脓毒症的小鼠肺部中的 ALI。 公共健康相关性：急性肺损伤通常与严重感染或失血有关，尽管 AMP 激活蛋白激酶（也称为 AMPK）在调节许多细胞代谢途径中发挥着核心作用，但我们和其他实验室的最新研究表明，AMPK 可以。减少炎症细胞的激活，我们已经证明 AMPK 激活可以降低内毒素引起的肺损伤的严重程度。本申请中提出的研究不仅应该增进对激活的 AMPK 预防肺功能障碍和死亡的细胞机制的理解。出血和脓毒症，但也可能提出新的治疗干预措施，旨在改善患有这些临床问题的患者的预后。