Mild hypothermia alleviates brain oedema and blood-brain barrier disruption by attenuating tight junction and adherens junction breakdown in a swine model of cardiopulmonary resuscitation.

Jiebin Li,Chunsheng Li,Yongzhen Zhao,Junyuan Wu,Zhenhua Li,Wei Yuan,Jie Li,Mária A Deli

doi:10.1371/journal.pone.0174596

Abstract

Mild hypothermia improves survival and neurological recovery after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). However, the mechanism underlying this phenomenon is not fully elucidated. The aim of this study was to determine whether mild hypothermia alleviates early blood–brain barrier (BBB) disruption. We investigated the effects of mild hypothermia on neurologic outcome, survival rate, brain water content, BBB permeability and changes in tight junctions (TJs) and adherens junctions (AJs) after CA and CPR. Pigs were subjected to 8 min of untreated ventricular fibrillation followed by CPR. Mild hypothermia (33°C) was intravascularly induced and maintained at this temperature for 12 h, followed by active rewarming. Mild hypothermia significantly reduced cortical water content, decreased BBB permeability and attenuated TJ ultrastructural and basement membrane breakdown in brain cortical microvessels. Mild hypothermia also attenuated the CPR-induced decreases in TJ (occludin, claudin-5, ZO-1) and AJ (VE-cadherin) protein and mRNA expression. Furthermore, mild hypothermia decreased the CA- and CPR-induced increases in matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression and increased angiogenin-1 (Ang-1) expression. Our findings suggest that mild hypothermia attenuates the CA- and resuscitation-induced early brain oedema and BBB disruption, and this improvement might be at least partially associated with attenuation of the breakdown of TJ and AJ, suppression of MMP-9 and VEGF expression, and upregulation of Ang-1 expression.

Highlights

Brain injury remains a significant source of morbidity in cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) survivors
There were no differences in baseline characteristics, including body weight, bladder temperature, ETCO2, central venous pressure (CVP), mean arterial pressure (MAP), heart rate, cardiac output, arterial oxygen pressure, arterial lactate and base excess, between the groups (P>0.05) (Table 1)
We employed a pig model and demonstrated that global cerebral ischaemia following CA and CPR resulted in blood-brain barrier (BBB) disruption and oedema in the cerebral cortex at 24 hours after Return of spontaneous circulation (ROSC)

Summary

Introduction

Brain injury remains a significant source of morbidity in cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) survivors. Mild hypothermia management has been shown to exert a variety of neuroprotective effects in CA patients and animals [4,5,6,7]. These protective effects may result from inhibition of inflammatory cytokines, brain metabolism and oxidative stress, reduction of mitochondrial membrane permeability, attenuation of neuronal apoptosis, amelioration of brain oedema and other processes [1,3,5,6,7,8]. Ischaemic injury decreases TJ integrity between endothelial cells in the brain, resulting in BBB breakdown and directly contributing to brain vasogenic oedema, haemorrhagic transformation and increased mortality [17,24]

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