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.
Acute lung injury is frequently associated with severe infection or blood loss. Although AMP activated protein kinase (also called AMPK) play 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 decreased 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.
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