Targeting AMPK to prevent lethal complications during sepsis
The barrier function of endothelium derives from the integrity of the endothelial structure that is provided by membrane intercellular junctions connected to the actin cytoskeleton and cell attachment to extracellular matrix and basement membrane. An alteration of these junctions and/or of the cytoskeleton organization/contraction promotes vascular hyper-permeability to fluid and solutes and can contribute significantly to the damage associated with a variety of pathological states such as sepsis. Sepsis is characterized by a systemic inflammatory response that occurs during severe infection. Increased microcirculatory permeability is a major complication in sepsis and contributes to end-organ dysfunction. Enhanced permeability can induce tissue oedema, impairing organ function by increasing the distance required for the diffusion of oxygen and by compromising microvascular perfusion because of increased interstitial pressure. From the above, the pivotal role of the microvascular barrier as a therapeutic target in sepsis seems obvious. A better understanding of the molecular basis of endothelial barrier function might lead to new molecular targets for therapies. The project, focused on the AMPK pathway, aims to evaluate how the modulation of endothelial permeabilty can affect the cardiovascular pathophysiology. Its feasibility is supported by the availability of key cellular and mouse models, pharmacological reagents, as well as characterized cohorts of patients.
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