Brain tight junction protein expression in sepsis in an autopsy series

Kristo Erikson,Tero Ilmari Ala-Kokko,Tuomo Karttunen,Hannu Syrjälä,Hannu Tuominen,Merja Vakkala,Janne Henrik Liisanantti

doi:10.1186/s13054-020-03101-3

Kristo Erikson, Tero Ilmari Ala-Kokko + Show 5 more

Open Access

https://doi.org/10.1186/s13054-020-03101-3

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Abstract

BackgroundNeuroinflammation often develops in sepsis along with increasing permeability of the blood-brain barrier (BBB), which leads to septic encephalopathy. The barrier is formed by tight junction structures between the cerebral endothelial cells. We investigated the expression of tight junction proteins related to endothelial permeability in brain autopsy specimens in critically ill patients deceased with sepsis and analyzed the relationship of BBB damage with measures of systemic inflammation and systemic organ dysfunction.MethodsThe case series included all (385) adult patients deceased due to sepsis in the years 2007–2015 with available brain specimens taken at autopsy. Specimens were categorized according to anatomical location (cerebrum, cerebellum). The immunohistochemical stainings were performed for occludin, ZO-1, and claudin. Patients were categorized as having BBB damage if there was no expression of occludin in the endothelium of cerebral microvessels.ResultsBrain tissue samples were available in 47 autopsies, of which 38% (18/47) had no expression of occludin in the endothelium of cerebral microvessels, 34% (16/47) developed multiple organ failure before death, and 74.5% (35/47) had septic shock.The deceased with BBB damage had higher maximum SOFA scores (16 vs. 14, p = 0.04) and more often had procalcitonin levels above 10 μg/L (56% vs. 28%, p = 0.045) during their ICU stay. BBB damage in the cerebellum was more common in cases with C-reactive protein (CRP) above 100 mg/L as compared with CRP less than 100 (69% vs. 25%, p = 0.025).ConclusionsIn fatal sepsis, damaged BBB defined as a loss of cerebral endothelial expression of occludin is related with severe organ dysfunction and systemic inflammation.

Highlights

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection [1]
It has been suggested that neuroinflammation develops in sepsis along with an activation of the cerebral endothelium, an increase in the permeability of the blood-brain barrier (BBB) and a promotion of neutrophil infiltration; all these abnormalities result in brain dysfunction [2, 3]
To gain more insight into the pathophysiology of brain dysfunction in human sepsis, we investigated the expression of proteins related to endothelial permeability in brain autopsy specimens in critically ill patients deceased with sepsis

Summary

Introduction

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection [1]. Several endogenous and exogenous substances, such as proinflammatory cytokines, reactive oxygen species, and bacterial toxins increase the permeability of TJs. Most of the studies far have been based on animal data and in vitro cell culture methods [8, 9], and there are only a limited number of human studies on BBB dysfunction in sepsis and association of the dysfunction with clinical features such as systemic level inflammation. Neuroinflammation often develops in sepsis along with increasing permeability of the blood-brain barrier (BBB), which leads to septic encephalopathy. We investigated the expression of tight junction proteins related to endothelial permeability in brain autopsy specimens in critically ill patients deceased with sepsis and analyzed the relationship of BBB damage with measures of systemic inflammation and systemic organ dysfunction

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