AMPK activation and acute lung injury

AMPK 激活与急性肺损伤

基本信息

批准号：
8603179
负责人：
Jaroslaw Waldemar Zmijewski
金额：
$ 35.89万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
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/8603179
关键词：
26S proteasome 5&apos -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 abstracting cytokine human FRAP1 protein improved knock-down lung injury macrophage mortality neutrophil novel therapeutic intervention prevent research study resistin response

项目摘要

Abstract 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 IkBa, SCF-bTrCP mediated ubiquitination of phosphorylated IkBa and degradation of ubiquitinated IkBa 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.

抽象的急性肺损伤 (ALI) 是一种病理生理过程，其中中性粒细胞和巨噬细胞发挥重要作用，经常与感染相关，但也可能出现其他诱发因素，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 激活的蛋白激酶 (AMPK) 在 TLR2 或 TLR4 刺激下具有有效的抗炎作用我们已经证明，中性粒细胞、巨噬细胞和其他与 ALI 相关的细胞群。激活 AMPK 的药物干预，即使在 TLR4 启动后使用诱导的 ALI，减轻肺损伤的严重程度，尽管 AMPK 激活通常是与代谢应激有关，特别是细胞内 ATP 水平降低或增强活性氧 (ROS) 的产生，未发现 AMPK 活性增加尽管 ATP:AMP 减少，但 ALI 或脓毒症诱导的 ALI 患者的临床前模型在这些环境中抑制活性氧形成的比率或增强的机制。目前尚不清楚 ALI 期间肺部的 AMPK，但可能会导致严重程度我们认为 AMPK 激活具有有效的抗炎作用，但这种作用会减弱。 ALI 的严重性以及 TLR2 中存在的反调节机制 TLR4 在 ALI 期间刺激肺部和中性粒细胞和巨噬细胞，从而预防该项目的具体目标是： 1）通过以下方式确定 AMPK 激活机制。 AMPK 的激活会降低 TLR2 和 TLR4 的促炎特性刺激中性粒细胞和肺泡巨噬细胞，减轻肺损伤的严重程度 2) 确定在TLR2或TLR4刺激中抑制AMPK激活的机制我们的目标是中性粒细胞和巨噬细胞以及 LPS 或脓毒症诱发的 ALI 模型。确定激活的 AMPK 在抑制 NF-¿ 核转位中的作用B、通过检查 AMPK 激活对 IkBa、SCF-bTrCP 介导的 IKK 依赖性磷酸化的影响磷酸化 IkBa 的泛素化和 26S 泛素化 IkBa 的降解我们还将确定激活的 AMPK 在调节中的作用。 mTORC1 功能，特别是 mTORC1 依赖性炎症介质的产生。此外，拟议的实验将检查抵抗素和 HMGB1 在预防 TLR2 或 TLR4 刺激的中性粒细胞和肺泡巨噬细胞以及患有 LPS 或脓毒症的小鼠的肺会诱发 ALI。