title: Systemic pro-inflammatory response facilitates the development of cerebral edema during short hypoxia.
abstract: BACKGROUND
  High-altitude cerebral edema (HACE) is the severe type of acute mountain sickness (AMS) and life threatening. A subclinical inflammation has been speculated, but the exact mechanisms underlying the HACE are not fully understood.
  
  
  METHODS
  Human volunteers ascended to high altitude (3860 m, 2 days), and rats were exposed to hypoxia in a hypobaric chamber (5000 m, 2 days). Human acute mountain sickness was evaluated by the Lake Louise Score (LLS), and plasma corticotrophin-releasing hormone (CRH) and cytokines TNF-α, IL-1β, and IL-6 were measured in rats and humans. Subsequently, rats were pre-treated with lipopolysaccharide (LPS, intraperitoneal (ip) 4 mg/kg, 11 h) to induce inflammation prior to 1 h hypoxia (7000 m elevation). TNF-α, IL-1β, IL-6, nitric oxide (NO), CRH, and aquaporin-4 (AQP4) and their gene expression, Evans blue, Na(+)-K(+)-ATPase activity, p65 translocation, and cell swelling were measured in brain by ELISA, Western blotting, Q-PCR, RT-PCR, immunohistochemistry, and transmission electron micrography. MAPKs, NF-κB pathway, and water permeability of primary astrocytes were demonstrated. All measurements were performed with or without LPS challenge. The release of NO, TNF-α, and IL-6 in cultured primary microglia by CRH stimulation with or without PDTC (NF-κB inhibitor) or CP154,526 (CRHR1 antagonist) were measured.
  
  
  RESULTS
  Hypobaric hypoxia enhanced plasma TNF-α, IL-1β, and IL-6 and CRH levels in human and rats, which positively correlated with AMS. A single LPS injection (ip, 4 mg/kg, 12 h) into rats increased TNF-α and IL-1β levels in the serum and cortex, and AQP4 and AQP4 mRNA expression in cortex and astrocytes, and astrocyte water permeability but did not cause brain edema. However, LPS treatment 11 h prior to 1 h hypoxia (elevation, 7000 m) challenge caused cerebral edema, which was associated with activation of NF-κB and MAPKs, hypoxia-reduced Na(+)-K(+)-ATPase activity and blood-brain barrier (BBB) disruption. Both LPS and CRH stimulated TNF-α, IL-6, and NO release in cultured rat microglia via NF-κB and cAMP/PKA.
  
  
  CONCLUSIONS
  Preexisting systemic inflammation plus a short severe hypoxia elicits cerebral edema through upregulated AQP4 and water permeability by TLR4 and CRH/CRHR1 signaling. This study revealed that both infection and hypoxia can cause inflammatory response in the brain. Systemic inflammation can facilitate onset of hypoxic cerebral edema through interaction of astrocyte and microglia by activation of TLR4 and CRH/CRHR1 signaling. Anti-inflammatory agents and CRHR1 antagonist may be useful for prevention and treatment of AMS and HACE.
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Institute of Neuroscience, School of Medicine, Key Laboratory of Medical Neurobiology of The Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Song
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Institute of Neuroscience, School of Medicine, Key Laboratory of Medical Neurobiology of The Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Bi
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Yu-Qi
authors.initials: YQ
authors.lastname: Gao
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Institute of Neuroscience, School of Medicine, Key Laboratory of Medical Neurobiology of The Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Huang
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Institute of Neuroscience, School of Medicine, Key Laboratory of Medical Neurobiology of The Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Institute of Neuroscience, School of Medicine, Key Laboratory of Medical Neurobiology of The Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Tang
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Institute of Neuroscience, School of Medicine, Key Laboratory of Medical Neurobiology of The Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Ma
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Institute of Neuroscience, School of Medicine, Key Laboratory of Medical Neurobiology of The Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Fan-Ping
authors.initials: FP
authors.lastname: Kong
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: John H
authors.initials: JH
authors.lastname: Coote
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Institute of Neuroscience, School of Medicine, Key Laboratory of Medical Neurobiology of The Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University, Hangzhou, 310058, China. chewyg@zju.edu.cn.
authors.forename: Xue-Qun
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, Institute of Neuroscience, School of Medicine, Key Laboratory of Medical Neurobiology of The Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University, Hangzhou, 310058, China. dujz@zju.edu.cn.
authors.forename: Ji-Zeng
authors.initials: JZ
authors.lastname: Du
mesh_terms: D000293:Adolescent; D000532:Altitude Sickness / Q000503:physiopathology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D001834:Body Water / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology* / Q000503:physiopathology*; D002463:Cell Membrane Permeability; D003346:Corticotropin-Releasing Hormone / Q000097:blood; D016207:Cytokines / Q000097:blood; D064368:Healthy Volunteers; D006801:Humans; D000860:Hypoxia / Q000150:complications* / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D003346:Corticotropin-Releasing Hormone