Blood-brain barrier changes in high altitude.
2016
Cerebral syndromes related to high-altitude exposure are becoming more frequent as the
number of trips to high altitudes has increased in the last decade. The commonest symptom is headache,
followed by acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), which can be
fatal. The pathophysiology of these syndromes is not fully understood. The classical "tight-fit
hypothesis" posits that there are some anatomical variations that would obstruct the sinovenous outflow
and worsen vasogenic edema and intracranial hypertension reactive to hypoxia. This could explain
microhemorrhages seen in autopsies. However, recent magnetic resonance imaging studies have
demonstrated some components of cytotoxic edema in HACE absent in AMS, suggesting a dysfunction
in water balance at the cellular level. Currently, the "red-ox theory" supports trigemino-vascular system
activation by free radicals formed after hypoxia and the consequent oxidative stress cascades. Apart
from trigemino-vascular system activation, free radicals can also provoke membrane destabilisation
mediated by lipid peroxidation, inflammation, and local hypoxia inducible factor-1α and vascular
endothelial growth factor activation, resulting in gross blood-brain barrier (BBB) dysfunction. Besides
alterations in endothelial cells such as increased pinocytotic vesicles and disassembly of interendothelial
tight junction proteins, capillary permeability may also increase with subsequent swelling of astrocyte
end-feet. In conclusion, although the pathophysiology of AMS and HACE is not completely understood,
recent evidence proposes a multifactorial entity, with brain swelling and compromise of the BBB
considered to play an important role. A fuller comprehension of these processes is crucial to reduce and
prevent BBB alterations during high-altitude exposure.
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