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Review
. 2013 Aug 15;4(6):517-24.
doi: 10.4161/viru.24906. Epub 2013 May 7.

Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS

Samir M Parikh  1
Affiliations
Review

Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS

Samir M Parikh. Virulence. .

Abstract

Dynamic changes in microvascular endothelial structure and function are pivotal in the acute inflammatory response, the body's rapid, coordinated effort to localize, sequester, and eliminate microbial invaders at their portal of entry. To achieve this, the endothelium becomes leaky and inflamed, providing innate immune cells and humoral effector molecules access to the site of infection. During sepsis this locally adaptive response becomes manifest throughout the body, leading to dangerous host consequences. Increased leakiness in the pulmonary circulation contributes to acute respiratory distress syndrome (ARDS), a complication of sepsis associated with 40% mortality. Understanding the molecular governance of vascular leak and inflammation has major diagnostic, prognostic, and potentially therapeutic implications for this common and pernicious disease. This review summarizes results from cell-based experiments, animal models, and observational human studies; together, these studies suggest that an endothelial receptor called Tie2 and its ligands, called angiopoietins, form a signaling axis key to the vascular dyshomeostasis that underlies sepsis.

Keywords: Tie-1; Tie-2; VE-PTP; VE-cadherin; acute respiratory distress syndrome; angiopoietin-1; angiopoietin-2; infection; permeability; sepsis; vascular leakage.

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Figures

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Figure 1. The angiopoietin–Tie-2 axis in sepsis and acute respiratory distress syndrome. In quiescence, clusters of angiopoietin-1 (Angpt-1) aggregate and activate the transmembrane receptor tyrosine kinase, Tie-2, which is highly specifically expressed on endothelial cells. Tie-2 signals into the cell to favor phenotypes such as fortification of barrier function. In sepsis, angiopoietin-2 (Angpt-2) is upregulated and is believed to antagonize Angpt-1. The tonic homeostatic signaling through Tie-2 (pTie-2, phosphorylated Tie-2) is attenuated, contributing to the vascular leak and inflammation observed in sepsis and related conditions.
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Figure 2. Angiopoietin-1 ameliorates endothelial barrier dysfunction induced by diverse ligands. The ability of excess angiopoietin-1 (Angpt-1) to prevent vascular leakage induced by diverse mediators of permeability, all of which act through unique cell surface receptors or have incompletely known mechanisms of action, suggests that Angpt-1-induced Tie-2 activation impacts a final common pathway for permeability, such as the remodeling of intercellular junctions and the actin cytoskeleton. PAF, platelet activating factor; TNFα, tumor necrosis factor α; LPS, lipopolysaccharides.
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