Elsevier

Brain, Behavior, and Immunity

Volume 64, August 2017, Pages 266-275
Brain, Behavior, and Immunity

Full-length Article
Hypoxia augments LPS-induced inflammation and triggers high altitude cerebral edema in mice

https://doi.org/10.1016/j.bbi.2017.04.013Get rights and content

Highlights

  • Inflammation may play vital roles in high altitude cerebral edema is proposed.

  • Hypoxia augments LPS-induced systemic inflammation and neuroinflammation.

  • Combination of hypoxia exposure and LPS injection rapidly induces cerebral edema.

  • Combination of hypoxia exposure and LPS injection induces blood-brain barrier leakage by disrupting tight junctions.

  • Combination of hypoxia exposure and LPS injection induces cognitive and motor dysfunction.

Abstract

High altitude cerebral edema (HACE) is a life-threatening illness that develops during the rapid ascent to high altitudes, but its underlying mechanisms remain unclear. Growing evidence has implicated inflammation in the susceptibility to and development of brain edema. In the present study, we investigated the inflammatory response and its roles in HACE in mice following high altitude hypoxic injury. We report that acute hypobaric hypoxia induced a slight inflammatory response or brain edema within 24 h in mice. However, the lipopolysaccharide (LPS)-induced systemic inflammatory response rapidly aggravated brain edema upon acute hypobaric hypoxia exposure by disrupting blood-brain barrier integrity and activating microglia, increasing water permeability via the accumulation of aquaporin-4 (AQP4), and eventually leading to impaired cognitive and motor function. These findings demonstrate that hypoxia augments LPS-induced inflammation and induces the occurrence and development of cerebral edema in mice at high altitude. Here, we provide new information on the impact of systemic inflammation on the susceptibility to and outcomes of HACE.

Introduction

High altitudes and mountains cover one-fifth of the earth’s surface. With advances in technology, millions of people travel to high altitude areas for recreational, religious, economic and military purposes (Gallagher and Hackett, 2004). High altitude is characterized by hypobaric hypoxia, decreased temperatures, lower humidity and increased ultraviolet radiation (Gallagher and Hackett, 2004, Netzer et al., 2013). Among these factors, hypobaric hypoxia is regarded as the main factor contributing to altitude-related illness, which is quite common in those who are not adequately acclimated (MacInnis et al., 2010, Rodway et al., 2003, Bailey et al., 2009). Altitude-related illnesses include acute mountain sickness (AMS), high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). Among these, HACE is the most serious and can be lethal (Gallagher and Hackett, 2004, Eide and Asplund, 2012). HACE often occurs in those who abruptly ascend to over 3000 m, but the lowest reported altitude known to induce HACE was 2100 m (Dickinson, 1979). The prevalence of HACE is estimated to be 0.5 to 1% among persons at altitudes of 4,000–5,000 m (Bärtsch and Swenson, 2013). HACE is regarded as the end-stage of AMS and is characterized by truncal ataxia and decreased consciousness. If the appropriate treatment is not received within a certain period of time, coma may evolve, followed by death within 24 h due to brain herniation (Hackett and Roach, 2001). However, the mechanisms that cause HACE symptoms remain elusive, and methods for the prevention and treatment of HACE are limited (Guo et al., 2014).

Inflammation plays important roles in many diseases. High altitude exposure is often associated with gastrointestinal disorders, inflammation and increased risk of infection (Kleessen et al., 2005). It was reported that the incidence of digestive system disease is quite high among high altitude residents and immigrants (Recavarren-Arce et al., 2005). A markedly higher incidence of AMS in mountaineers with respiratory or gastrointestinal infections has also been reported (Murdoch, 1995). Murdoch also identified that the frequency of infectious symptoms was positively related to Lake Louise scores. A retrospective study in Colorado reported that 79% of HAPE patients had preexisting inflammation-inducing illness (Durmowicz et al., 1997). In viral infections, pulmonary edema is induced by hypoxia (Carpenter et al., 1998). It was recently reported that plasma TNF-α, IL-1β and IL-6 levels significantly increased when volunteers ascended to an altitude of 3860 m. A growing number of reports have also shown that inflammation plays a vital role in altitude-related illness (Song et al., 2016). However, the relationship between inflammation and HACE has been rarely investigated.

In the present study, we first investigated the potential role of systemic inflammation in the development of HACE. We found that acute hypobaric hypoxia (AHH) exposure significantly augmented lipopolysaccharide (LPS)-induced systemic inflammation. Cerebral edema, blood brain barrier (BBB) disruption, and neurological injury were induced after pretreatment with low doses of LPS followed by AHH exposure, whereas neither low-dose LPS injection nor AHH exposure alone induced marked effects. These results indicate that systemic inflammation induced by LPS aggravates brain edema under AHH exposure by disrupting BBB integrity and activating microglia, thus causing an accumulation of aquaporin-4 (AQP4) that increases water permeability and leads to impaired cognitive and motor function in mice. These findings demonstrate that the inflammatory response plays vital roles in the occurrence and development of HACE and provide a novel and efficient HACE mouse model for further studies.

Section snippets

Animals

Male adult 8-week-old C57BL/6 mice were supplied by the Vital River Experimental Animal Company, Beijing. Animals were maintained in the animal house of the Beijing Institute of Basic Medical Sciences and were housed at a constant temperature under a 12-h light-dark cycle with unlimited access to standard diet and water. The animal protocol was approved by the Institutional Animal Care and Use Committee of the Institute of Basic Medical Sciences.

LPS administration and AHH exposure

For LPS administration, the mice were subjected

AHH alone induces a slight inflammatory response and brain edema in mice

To explore whether exposure to AHH induced inflammation at the early stage of the ascent to the plateau, adult mice were exposed to a decompression chamber mimicking an altitude of 6000 m (equivalent to 10.16% O2 at sea level) for 6 h, 12 h and 24 h to acutely induce hypoxic brain injury. We then examined changes in the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α after exposure to AHH. Real-time PCR and ELISA were used to measure the gene expression and concentrations of these cytokines. The

Discussion

In this study, we found that hypoxia augments LPS-induced inflammation and triggers HACE, and we illuminated the potential mechanisms by which AHH exposure induces cerebral edema in mice (Fig. 7). We demonstrated that the inflammatory response accelerates the occurrence and development of brain edema under AHH exposure, which is associated with increased BBB permeability, microglial activation, and the enhanced expression of the water channel AQP-4, ultimately leading to impaired cognitive and

Declarations

Ethics approval and consent to participate: All study procedures involving animals were performed in accordance with the ethical standards of the Institutional Research Committee. Mice were maintained at the animal facility with free access to water and food in accordance with institutional guidelines. The Institutional Animal Care and Use Committee (IACUC) of the Academy of Beijing Medical Sciences approved all the experiments involving mice.

Consent for publication

Not applicable.

Availability of data and materials

The reproducible materials described in this manuscript, including any new software, databases and all relevant raw data, are freely available to any scientist wishing to use them, without breaching participant confidentiality.

Competing interests

The authors declare that they have no conflicts of interest.

Funding

This work was supported by grants from the Natural Science Foundation of China (Nos. 81430044 and 31370022), the Beijing Natural Science Foundation (No. 5132025), and the National Basic Research Program of China (Nos. 2011CB910800 and 2012CB518200).

Authors’ contributions

Yan Zhao Zhou: performed the research, analyzed the data; Xin Huang: designed the research, performed the research, analyzed the data, wrote the paper; Tong Zhao: contributed new reagents or analytic tools; Meng Qiao: contributed new reagents or analytic tools; Xingnan Zhao: analyzed the data; Ming Zhao: analyzed the data, contributed new reagents or analytic tools; Lun Xu: contributed new reagents or analytic tools; Yongqi Zhao: analyzed the data; Liying Wu: contributed new reagents or

Acknowledgments

This work was supported by grants from the Natural Science Foundation of China (Nos. 81430044 and 31370022), the Beijing Natural Science Foundation (No. 5132025), and the National Basic Research Program of China (Nos. 2011CB910800 and 2012CB518200).

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