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

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: :

• angiopoietin-1
• angiopoietin-2
• Tie-2
• Tie-1
• VE-PTP
• VE-cadherin
• permeability
• vascular leakage
• sepsis
• infection
• acute respiratory distress syndrome

Disclosure of Potential Conflicts of Interest

Dr Parikh is listed as an inventor on disclosures regarding angiopoietins filed with Beth Israel Deaconess Medical Center.

Acknowledgments

The author would like to thank Drs Ananth Karumanchi, Sascha David, and Chandra Ghosh for critical feedback. Dr Parikh is supported by NIH grants R01-HL093234 and R01-DK095072 and by the American Diabetes Association (1-13-BS-141).