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

Zhou, Yanzhao; Huang, Xin; Zhao, Tong; Qiao, Meng; Zhao, Xingnan; Zhao, Ming; Xu, Ling; Zhao, Yong-Qi; Wu, Liying; Wu, Kuiwu; Chen, Ruoli; Fan, Ming; Zhu, Lijing

doi:10.1016/j.bbi.2017.04.013

Cited by 87 publications

(70 citation statements)

References 30 publications

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“…Now, we have shown an association between CXCR-4 mRNA expression and increased LLS after 24 h at hypobaric hypoxia. Further studies are needed to analyze whether the CXCR-4/SDF-1 signaling pathway is induced in AMS and HACE and whether this is associated with increased passover of lymphocytes through the blood-brain barrier [34].…”

Section: Discussionmentioning

confidence: 99%

“…Especially, in high altitude cerebral edema (HACE) proinflammatory cytokines like IL-1β, IL-6, or vascular endothelial growth factor A (VEGF-A) are believed to play an important role [30,31]. Apart from pro-and anti-inflammatory cytokines, the role of chemokines is of particular importance, as chemokine expression and its ligands are crucial for immune cell migration, e.g., in neuroinflammatory processes, and could therefore also be of interest with respect to hypobaric hypoxia-induced AMS and high altitude cerebral edema (HACE) [32][33][34].…”

Section: Introductionmentioning

confidence: 99%

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Hypoxic-Inflammatory Responses under Acute Hypoxia: In Vitro Experiments and Prospective Observational Expedition Trial

Kämmerer

Faihs

Hulde

et al. 2020

IJMS

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Induction of hypoxia-inducible-factor-1α (HIF-1α) pathway and HIF-target genes allow adaptation to hypoxia and are associated with reduced incidence of acute mountain sickness (AMS). Little is known about HIF-pathways in conjunction with inflammation or exercise stimuli under acute hypobaric hypoxia in non-acclimatized individuals. We therefore tested the hypotheses that (1) both hypoxic and inflammatory stimuli induce hypoxic-inflammatory signaling pathways in vitro, (2) similar results are seen in vivo under hypobaric hypoxia, and (3) induction of HIF-dependent genes is associated with AMS in 11 volunteers. In vitro, peripheral blood mononuclear cells (PBMCs) were incubated under hypoxic (10%/5% O2) or inflammatory (CD3/CD28) conditions. In vivo, Interleukin 1β (IL-1β), C-X-C Chemokine receptor type 4 (CXCR-4), and C-C Chemokine receptor type 2 (CCR-2) mRNA expression, cytokines and receptors were analyzed under normoxia (520 m above sea level (a.s.l.)), hypobaric hypoxia (3883 m a.s.l.) before/after exercise, and after 24 h under hypobaric hypoxia. In vitro, isolated hypoxic (p = 0.004) or inflammatory (p = 0.006) stimuli induced IL-1β mRNA expression. CCR-2 mRNA expression increased under hypoxia (p = 0.005); CXCR-4 mRNA expression remained unchanged. In vivo, cytokines, receptors, and IL-1β, CCR-2 and CXCR-4 mRNA expression increased under hypobaric hypoxia after 24 h (all p ≤ 0.05). Of note, proinflammatory IL-1β and CXCR-4 mRNA expression changes were associated with symptoms of AMS. Thus, hypoxic-inflammatory pathways are differentially regulated, as combined hypoxic and exercise stimulus was stronger in vivo than isolated hypoxic or inflammatory stimulation in vitro.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypoxic-Inflammatory Responses under Acute Hypoxia: In Vitro Experiments and Prospective Observational Expedition Trial

Kämmerer

Faihs

Hulde

et al. 2020

IJMS

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“…Thus, neutrophils recruited in large numbers to these disease-associated tissues or trapped in areas of microcirculatory impairment are exposed to profound levels of hypoxia. As well as being a consequence of inflammation, hypoxia can drive inflammatory processes; increased vascular leak and endothelial damage, and impaired resolution of infection have been demonstrated in hypoxic mice [18][19][20] or following ischaemic injury (where the interrupted blood supply causes tissue hypoxia) in various organs [21], and increased circulating pro-inflammatory cytokines are detected in humans at high altitude, where hypoxia is secondary to reduced atmospheric oxygen levels [22].…”

Section: The Relevance Of Hypoxia To Neutrophilsmentioning

confidence: 99%

The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host

Lodge

Cowburn

et al. 2020

IJMS

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Neutrophils are key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. Neutrophils may kill pathogens intracellularly, following phagocytosis, or extracellularly, by degranulation and the release of neutrophil extracellular traps; all of these microbicidal strategies require the deployment of cytotoxic proteins and proteases, packaged during neutrophil development within cytoplasmic granules. Neutrophils operate in infected and inflamed tissues, which can be profoundly hypoxic. Neutrophilic infiltration of hypoxic tissues characterises a myriad of acute and chronic infectious and inflammatory diseases, and as well as potentially protecting the host from pathogens, neutrophil granule products have been implicated in causing collateral tissue damage in these scenarios. This review discusses the evidence for the enhanced secretion of destructive neutrophil granule contents observed in hypoxic environments and the potential mechanisms for this heightened granule exocytosis, highlighting implications for the host. Understanding the dichotomy of the beneficial and detrimental consequences of neutrophil degranulation in hypoxic environments is crucial to inform potential neutrophil-directed therapeutics in order to limit persistent, excessive, or inappropriate inflammation.

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“…As the brain links all of the peripheral organs, brain ischaemia can affect function throughout the body, whereas alterations in peripheral organ function also affect the brain. For example, the immune system is suppressed after ischaemic stroke [5][6][7][8], whereas systemic infection aggravates brain oedema in hypoxia [9]. Up to 95% of stroke patients develop systemic (medical) complications [10,11] and/or neurological complications, as well as stroke syndromes [12,13].…”

Section: Introductionmentioning

confidence: 99%

Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy

et al. 2020

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Microglia, the major endogenous immune cells of the central nervous system, mediate critical degenerative and regenerative responses in ischaemic stroke. Microglia become “activated”, proliferating, and undergoing changes in morphology, gene and protein expression over days and weeks post-ischaemia, with deleterious and beneficial effects. Pro-inflammatory microglia (commonly referred to as M1) exacerbate secondary neuronal injury through the release of reactive oxygen species, cytokines and proteases. In contrast, microglia may facilitate neuronal recovery via tissue and vascular remodelling, through the secretion of anti-inflammatory cytokines and growth factors (a profile often termed M2). This M1/M2 nomenclature does not fully account for the microglial heterogeneity in the ischaemic brain, with some simultaneous expression of both M1 and M2 markers at the single-cell level. Understanding and regulating microglial activation status, reducing detrimental and promoting repair behaviours, present the potential for therapeutic intervention, and open a longer window of opportunity than offered by acute neuroprotective strategies. Pharmacological modulation of microglial activation status to promote anti-inflammatory gene expression can increase neurogenesis and improve functional recovery post-stroke, based on promising preclinical data. Cell-based therapies, using preconditioned microglia, are of interest as a method of therapeutic modulation of the post-ischaemic inflammatory response. Currently, there are no clinically-approved pharmacological options targeting post-ischaemic inflammation. A major developmental challenge for clinical translation will be the selective suppression of the deleterious effects of microglial activity after stroke whilst retaining (or enhancing) the neurovascular repair and remodelling responses of microglia.

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

Cited by 87 publications

References 30 publications

Hypoxic-Inflammatory Responses under Acute Hypoxia: In Vitro Experiments and Prospective Observational Expedition Trial

Hypoxic-Inflammatory Responses under Acute Hypoxia: In Vitro Experiments and Prospective Observational Expedition Trial

The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host

Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy

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