The vasculature in sepsis: delivering poison or remedy to the brain?

Abstract

Survivors of sepsis and other forms of critical illness frequently experience significant and disabling cognitive and affective disorders. Inflammation, ischemia, and glial cell dysfunction contribute to this persistent brain injury. In this issue of the JCI, Hippensteel et al. show that endothelial injury in animal models of sepsis or endotoxemia leads to shedding of heparan fragments from the endothelial glycocalyx. These fragments directly sequester brain-derived neurotrophic factor and impair hippocampal long-term potentiation, an electrophysiologic correlate of memory. The authors further explore the specific characteristics of heparan fragments that bind neurotrophins and the presence of these fragments in the circulation of patients who survive sepsis. This study highlights an important mechanism by which vascular injury can impair brain function.

Figure 1. Injury to the endothelial glycocalyx in sepsis results in the release of heparan sulfate fragments into the brain parenchyma.

Heparan sulfate fragments then bind and sequester BDNF, preventing activation of the TrkB receptor and leading to the loss of downstream TrkB signaling and protein synthesis that support synaptic strengthening during LTP. Illustrated by Rachel Davidowitz.