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（由适用提供）：急性肺损伤（ALI）是一种病理生理过程，其中激活的中性粒细胞和巨噬细胞扮演着重要的作用，经常与感染有关，但也可能来自其他诱发事件，包括出血，燃烧，烧伤或受伤的机械通气。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）的激活在TLR2或TLR4刺激的中性粒细胞，巨噬细胞和其他与Ali相关的细胞群中具有潜在的抗炎作用。我们已经表明，即使在启动TLR4诱导的ALI之后使用，也会激活AMPK的药理学干预措施，从而减少了肺损伤的严重程度。尽管AMPK激活通常与代谢应激有关，尤其是细胞内ATP水平的降低或增强活性氧（ROS）的产生，但在ALI的临床前模型中未发现AMPK活性的增加，或者在脓毒症诱导的ALI患者中，ATP：AMP：AMP：AMP比率的降低或增强的ROS玫瑰在这些设置中的降低。抑制ALI期间肺中AMPK激活的机制目前尚不清楚，但可能有助于ALI的严重程度。我们假设AMPK激活具有潜在的抗炎作用，从而降低了ALI的严重程度，并且还假设TLR2和TLR4中存在反调节机制，刺激了嗜中性粒细胞和巨噬细胞，以及在ALI中刺激了ALI的肺部，从而阻止了AMPK激活。该项目的具体目的是：1）确定AMPK激活降低TLR2和TLR4的促炎特性的机制，刺激了嗜中性粒细胞和肺泡巨噬细胞，并减少肺部损伤的严重性，并确定AMPK在TLR2或TLR2激活中的机制。 LPS或败血症引起的ALI。我们的目标是通过检查AMPK激活对IKK依赖性I-ba的IKK依赖性磷酸化的影响来确定激活AMPK在抑制NF-？B的核转运中的作用，SCF-€trcp介导的磷酸化I？我们还将确定激活AMPK在调节MTORC1功能的调节中的作用，尤其是MTORC1依赖性炎症介体的产生。此外，提出的实验将检查抵抗蛋白和HMGB1在防止TLR2或TLR4中AMPK激活的作用，刺激了中性粒细胞和肺泡巨噬细胞以及LPS或败血症诱导的Ali的小鼠肺中的肺泡巨噬细胞。 公共卫生相关性：急性肺损伤经常与严重感染或失血有关。尽管AMP激活的蛋白激酶（也称为AMPK）在确定许多细胞代谢途径中起着核心作用，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，我们已经表明AMPK激活可以降低内毒素诱导的肺损伤的严重程度。该应用中提出的研究不仅应提高对激活AMPK的细胞机制的理解，这些AMPK可防止肺功能障碍和出血和败血症后的肺功能障碍和死亡，而且还可能表明旨在改善患有这些临床问题的患者的结果。