Vascular leak in sepsis: physiological basis and potential therapeutic advances

Abstract

Sepsis is a life-threatening condition characterised by endothelial barrier dysfunction and impairment of normal microcirculatory function, resulting in a state of hypoperfusion and tissue oedema. No specific pharmacological therapies are currently used to attenuate microvascular injury. Given the prominent role of endothelial breakdown and microcirculatory dysfunction in sepsis, there is a need for effective strategies to protect the endothelium. In this review we will discuss key mechanisms and putative therapeutic agents relevant to endothelial barrier function.

Keywords: Endothelial dysfunction; Oedema; Sepsis.

Fig. 1

Endothelial cell–cell junction complexes. These key junctional structures maintain endothelial barrier integrity. The ZO proteins link the membrane proteins to the filamentous cytoskeleton. Members of the Rho family of GTPases mediate opposing changes in endothelial cell permeability with Rac1 stabilising the VE-cadherin complex and RhoA de-stabilising the VE-cadherin complex

Fig. 2

An array of microbial components stimulate the innate immune response by activating Toll-like receptors which results in the nuclear translocation of the transcription factor NF-κB. NF-κB then promotes the expression of pro-inflammatory cytokines such as TNF- α which induces endothelial cell dysfunction

Fig. 3

The sepsis state results in vascular leakage due to a combination of glycocalyx degradation and cell–cell disruption. The loss of glycocalyx and endothelial integrity results in the transvascular loss of albumin which favours vascular leakage

Fig. 4

In sepsis Ang-2 acts as an antagonist of Tie 2 which results in disruption of protective Ang-1/Tie 2 signalling. The antagonistic effects of Ang-2 leads to increased inflammation and inhibition of the vascular stabilising Akt signalling pathway. Moreover, the vascular barrier protective effects of Tie 2 are abrogated by the cleaving properties of MMP14

Fig. 5

Normal oxygen diffusion from blood vessels to target tissue cells. b Tissue hypoxia occurring due to increased diffusion distance between oxygen carrying red blood cells in the microvascular blood vessels and the mitochondria of tissue cells. c Tissue hypoxia occurring due to a tamponade like effect of interstitial fluid on microvascular blood vessels