Systemic Inflammation Facilitates The Development Of High-altitude Cerebral Edema

Inflammation plays a crucial role in neurological disease. Clinically, inflammation is thought to promote the occurrence of AMS. HACE is the serious disease in AMS, although uncommon, HACE causes significant morbidity and occasionally death. The pathogenesis of HACE is unclear. Here, we use human and rat to study inflammatory response induced by hypoxia, and use rat primary astrocytes to explore the cell membrane permeability changed by inflammation and the signaling pathway. Our data showed high altitude hypoxia induced AMS in human and increase of cytokines (TNF-α, IL-1β and IL-6) in blood, and cytokines increase positively correlated with AMS. In rats, intraperitoneal injection of LPS induced systemic inflammation, and hypobaric hypoxia chamber simulated high altitude. Neither LPS stimulation alone for 12 h nor hypobaric altitude of 7000 m alone for 1h induced rats cerebral edema, but rats exposed to a combination of both stimuli exhibited increased brain water content. Pathological brain cortex slice showed cell swelling and enlarged perivascular space. Morphologically, LPS+Hypoxia significantly induced astrocytes swelling, intracellular mitochondrial swelling and mitochondrial membrane rupture as observed by transmission electron microscopy. In vivo experiment, hypoxia decreased Na+/K+-ATPase activity of brain cortex, suggesting hypoxia resulted in higher osmotic pressure inside the cell by reducing brain Na+/K+-ATPase activity, so as to drive the astrocyte edema. In vitro experiment also proved hypotonic of extracelluar environment caused astrocyte swelling, and LPS markedly promoted osmotically-driven astrocytic swelling through high expression of AQP4. LPS and cytokines TNF-α or IL-1β upregulated AQP4 by activiting p65 and MAPK, demonstrating TLR4 (Toll-like receptor 4) pathway was involved in astrocyte swelling. Thus, systemic inflammation enhances the formation of cerebral cytotoxic edema through activating TLR4 pathway to upregulate AQP4, eventually leading to the development of hypoxic cerebral edema.