Bench-to-bedside review: The role of activated protein C in maintaining endothelial tight junction function and its relationship to organ injury

Mark R Looney,Michael A Matthay

doi:10.1186/cc5099

Mark R Looney, Michael A Matthay

Open Access

https://doi.org/10.1186/cc5099

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Journal: Critical Care	Publication Date: Jan 1, 2006
Citations: 62	License type: unspecified-oa

Affiliation: University of California, San Francisco

Abstract

Activated protein C (APC) has emerged as a novel therapeutic agent for use in selected patients with severe sepsis, even though the mechanism of its benefit is not well established. APC has anticoagulant, anti-inflammatory, antiapoptotic, and profibrinolytic properties, but it is not clear through which of these mechanisms APC exerts its benefit in severe sepsis. Focus has recently turned to the role of APC in maintaining endothelial barrier function, and in vitro and in vivo studies have examined this relationship. This article critically reviews these studies, with a focus on potential mechanisms of action.

Highlights

A defining feature of sepsis and the related acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is damage to the microvascular endothelium leading to altered blood flow, oxygen extraction, and increased permeability to protein and solutes [1,2,3]
The pathogenesis of organ injury in ALI/ARDS is similar to the proposed mechanisms for septic-induced injury, and so it is conceivable that Activated protein C (APC) may exert anticoagulant, antiinflammatory, antiapoptotic, or barrier-enhancing effects that
Apoptosis appears to be a significant mechanism contributing to endothelial dysfunction in sepsis, and APC has well described direct antiapoptotic properties that are independent of its anticoagulant activity

Summary

Introduction

A defining feature of sepsis and the related acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is damage to the microvascular endothelium leading to altered blood flow, oxygen extraction, and increased permeability to protein and solutes [1,2,3]. Low-dose mouse APC produced in vivo neuroprotection, independent of its anticoagulant activity Another direct mechanism of action of APC on the endothelium is modulation of the endothelial monolayer, leading to increased cell-cell contact and decreased permeability. Acid-induced lung injury produces damage to the alveolar epithelium and prominent lung vascular permeability to protein [36] This model of lung injury is very neutrophil dependent and is a good choice for testing the direct and indirect effects of APC on the lung microvasculature. The pathogenesis of organ injury in ALI/ARDS is similar to the proposed mechanisms for septic-induced injury, and so it is conceivable that APC may exert anticoagulant, antiinflammatory, antiapoptotic, or barrier-enhancing effects that. If the results are encouraging, a phase III randomized trial could be conducted to test the potential value of APC in ALI in a large number of patients

Conclusion

Esmon C