Circulating heparan sulfate fragments mediate septic cognitive dysfunction

Hippensteel, Joseph A.; Anderson, Brian J.; Orfila, James E; McMurtry, Sarah A.; Dietz, Robert M.; Su, Guowei; Ford, Joshay A.; Oshima, Kêichi; Yang, Yimu; Zhang, Fuming; Han, Xianlin; Yu, Yanlei; Liu, Jian; Linhardt, Robert J.; Meyer, Nuala J.; Herson, Paco S.; Schmidt, Eric P.

doi:10.1172/jci124485

Cited by 87 publications

(96 citation statements)

References 30 publications

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“…Rapid clearance of circulating heparan sulfate fragments occurs in septic animals despite impairment in urinary heparan sulfate clearance, suggesting that oligosaccharides may be cleared by alternative mechanisms, such as transvascular leakage into tissues. The penetration of heparan sulfate into tissues is clinically relevant, as sepsis-associated circulating heparan sulfate oligosaccharides are of sufficient size (∼6-10 saccharides) and sulfation (enriched in N-sulfation) to bind to growth factors, potentially influencing downstream signaling processes of relevance to both organ injury onset and repair (8).…”

Section: Discussionmentioning

confidence: 99%

“…growth factor necessary for spatial memory formation. Accordingly, the presence of circulating heparan sulfate in septic patients predicts persistent impairments in cognitive function (8). The degree to which circulating heparan sulfate selectively penetrates the hippocampus in comparison with other neuronal (brain cortex) and nonneuronal (e.g., lung, fat, liver, kidney, etc.)…”

Section: Significancementioning

confidence: 99%

“…The bedside detection of glycocalyx degradation during sepsis (mediated by "sheddases" such as heparanase, a mammalian endoglucuronidase acting on heparan sulfate) has been largely performed by measuring glycocalyx breakdown products (e.g., highly sulfated, heparin-like, heparan sulfate fragments, approximately octasaccharide to decasaccharide in size) in the plasma of septic patients (4). However, as heparan sulfate fragments can persist in the plasma for up to 7 d after sepsis onset (4,8), it is uncertain whether the persistence of circulating heparan sulfate fragments reflects ongoing glycocalyx degradation or rather sepsis-associated impairment in the endogenous processes of plasma heparan sulfate clearance. For circulating heparan sulfate fragments to retain their value as biomarkers of ongoing glycocalyx injury, it is necessary to determine the half-life of circulating heparan sulfate in a septic host.…”

mentioning

confidence: 99%

“…We have recently demonstrated that sepsis induces accumulation of circulating, highly sulfated heparan sulfate fragments within the hippocampus, a region of the brain implicated in memory formation (8). In both mice and humans, hippocampal-penetrating heparan sulfate was of sufficient size and sulfation to sequester and inhibit the activity of brain-derived neurotrophic factor (BDNF), a…”

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confidence: 99%

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Circulating heparin oligosaccharides rapidly target the hippocampus in sepsis, potentially impacting cognitive functions

Zhang

Han

Xia

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Sepsis induces heparanase-mediated degradation of the endothelial glycocalyx, a heparan sulfate-enriched endovascular layer critical to vascular homeostasis, releasing highly sulfated domains of heparan sulfate into the circulation. These domains are oligosaccharides rich in heparin-like trisulfated disaccharide repeating units. Using a chemoenzymatic approach, an undecasaccharide containing a uniformly 13C-labeled internal 2-sulfoiduronic acid residue was synthesized on a p-nitrophenylglucuronide acceptor. Selective periodate cleavage afforded a heparin nonasaccharide having a natural structure. This 13C-labeled nonasaccharide was intravenously administered to septic (induced by cecal ligation and puncture, a model of polymicrobial peritonitis-induced sepsis) and nonseptic (sham) mice. Selected tissues and biological fluids from the mice were harvested at various time points over 4 hours, and the 13C-labeled nonasaccharide was recovered and digested with heparin lyases. The resulting 13C-labeled trisulfated disaccharide was quantified, without interference from endogenous mouse heparan sulfate/heparin, using liquid chromatography–mass spectrometry with sensitive and selective multiple reaction monitoring. The 13C-labeled heparin nonasaccharide appeared immediately in the blood and was rapidly cleared through the urine. Plasma nonasaccharide clearance was only slightly prolonged in septic mice (t1/2 ∼ 90 minutes). In septic mice, the nonasaccharide penetrated into the hippocampus but not the cortex of the brain; no hippocampal or cortical brain penetration occurred in sham mice. The results of this study suggest that circulating heparan sulfates are rapidly cleared from the plasma during sepsis and selectively penetrate the hippocampus, where they may have functional consequences.

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Circulating heparin oligosaccharides rapidly target the hippocampus in sepsis, potentially impacting cognitive functions

Zhang

Han

Xia

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Cognitive dysfunction has been associated with vascular injury during sepsis, but this has usually been framed in terms of hemodynamic impairment or loss of barrier function (14,22). The complex relationships among peripherally derived inflammatory mediators and leukocytes, microglia, and astrocytes in sepsis survivors that impinge on neuronal function depend on cascades of signaling pathways and changes in transcriptional programs that alter intrinsic neuronal function and expression of neurotrophins and physical-direct mechanism: sequestration of BDNF by products of endothelial glycocalyx injury (20). The endothelial glycocalyx is a meshwork of extracellular protein and carbohydrate molecules that supports endothelial function (21).…”

Section: Endothelial Injury Products In Future Studies Of Brain Injurymentioning

confidence: 99%

The vasculature in sepsis: delivering poison or remedy to the brain?

Singer¹

2019

Journal of Clinical Investigation

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Persistent brain injury in sepsis survivors Mortality from sepsis has fallen markedly with improvements in supportive care (1). Although over 14 million patients survive a hospitalization for sepsis each year, they are still not made whole by the life-saving care they receive (2). Rather, sepsis survivors frequently experience functional disability, along with increased risk of rehospitalization and death. Persistent brain dysfunction is a common and life-changing consequence of critical illness survivorship and results in both cognitive decline and a high incidence of affective disorders such as anxiety, depression, and posttraumatic stress (3, 4). Multiple factors contribute to persistent brain dysfunction in sepsis survivors. Neuropathologic studies of sepsis in patients have largely been confined to those who succumb to their acute illness and have revealed that ischemia, hemorrhage, and white matter injury commonly occur at the extremes of critical illness (5).

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