Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis

Flierl, Michael A.; Stahel, Philip F.; Rittirsch, Daniel; Huber‐Lang, Markus; Niederbichler, Andreas D.; Hoesel, Laszlo M.; Touban, Basel M.; Morgan, Steven J.; Smith, Wade R.; Ward, Peter A.; Ipaktchi, Kyros

doi:10.1186/cc7710

Cited by 91 publications

(79 citation statements)

References 79 publications

(60 reference statements)

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“…Compromised barrier integrity was evidenced in animal model and human sepsis by monitoring the levels or transport of various markers in the brain parenchyma (Jeppsson et al, 1981;Siami et al, 2008). Various cytokines released by activated leukocytes were shown to induce increased pinocytosis by endothelial cells (Anda et al, 1997;Huynh and Dorovini-Zis, 1993) and recently a central role of complement components (C5a) in blood-brain barrier dysfunction in sepsis was shown (Flierl et al, 2009). Apparent diffusion coefficients measured in the cortex and thalamus of septic animals indicated alterations in this parameter, which were related to the outcome.…”

Section: Discussionmentioning

confidence: 99%

Sepsis-Associated Encephalopathy: A Magnetic Resonance Imaging and Spectroscopy Study

Bozza

Garteiser

Oliveira

et al. 2009

J Cereb Blood Flow Metab

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Brain dysfunction is frequently observed in sepsis as a consequence of changes in cerebral structure and metabolism, resulting in worse outcome and reduced life-quality of surviving patients. However, the mechanisms of sepsis-associated encephalopathy development and a better characterization of this syndrome in vivo are lacking. Here, we used magnetic resonance imaging (MRI) techniques to assess brain morphology and metabolism in a murine sepsis model (cecal ligation and puncture, CLP). Sham-operated and CLP mice were subjected to a complete MRI session at baseline, 6 and 24 h after surgery. Accumulation of vasogenic edematic fluid at the base of the brain was observed in T 2 -weighted image at 6 and 24 h after CLP. Also, the water apparent diffusion coefficients in both hippocampus and cortex were decreased, suggesting a cytotoxic edema in brains of nonsurvival septic animals. Moreover, the N-acetylaspartate/choline ratio was reduced in brains of septic mice, indicating neuronal damage. In conclusion, noninvasive assessment by MRI allowed the identification of new aspects of brain damage in sepsis, including cytotoxic and vasogenic edema as well as neuronal damage. These findings highlight the potential applications of MRI techniques for the diagnostic and therapeutic studies in sepsis.

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Section: Discussionmentioning

confidence: 99%

Sepsis-Associated Encephalopathy: A Magnetic Resonance Imaging and Spectroscopy Study

Bozza

Garteiser

Oliveira

et al. 2009

J Cereb Blood Flow Metab

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show abstract

“…In this regard, some agents with anti-inflammatory action were useful to reduce LPS-induced microglial/astrocyte activation, production of pro-inflammatory mediators and facilitating recovery from neurobehavioural symptoms [11,56,84,118]. Likewise, in models of experimental sepsis there is evidence that blockage of C5a, a small peptide derived from complement activation, can prevent BBB breakdown [45]. It remains to be determined how these findings can be applied to humans.…”

Section: Perspectives On Prevention and Treatment Of Deliriummentioning

confidence: 99%

The neuroinflammatory hypothesis of delirium

et al. 2010

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Delirium is a neuropsychiatric syndrome characterized by a sudden and global impairment in consciousness, attention and cognition. It is particularly frequent in elderly subjects with medical or surgical conditions and is associated with short-and long-term adverse outcomes. The pathophysiology of delirium remains poorly understood as it involves complex multi-factorial dynamic interactions between a diversity of risk factors. Several conditions associated with delirium are characterized by activation of the inflammatory cascade with acute release of inflammatory mediators into the bloodstream. There is compelling evidence that acute peripheral inflammatory stimulation induces activation of brain parenchymal cells, expression of proinflammatory cytokines and inflammatory mediators in the central nervous system. These neuroinflammatory changes induce neuronal and synaptic dysfunction and subsequent neurobehavioural and cognitive symptoms. Furthermore, ageing and neurodegenerative disorders exaggerate microglial responses following stimulation by systemic immune stimuli such as peripheral inflammation and/or infection. In this review we explore the neuroinflammatory hypothesis of delirium based on recent evidence derived from animal and human studies.

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“…Lipophilic antibiotics (e.g., fluoroquinolones, macrolides, tigecycline, and lincosamides) have lesser alterations in the volume of distribution but can also develop reduced drug clearances, causing an increase of the AUC in plasma (207). In experimental animals sepsis increased cerebral albumin extravasation as an indicator of the impaired integrity of the blood-brain/ blood-CSF barrier (69,92). Therefore, in the majority of cases, sepsis should lead to a moderate increase in the concentrations of anti-infectives in the CSF and other intracranial compartments.…”

Section: Penetration Of Anti-infectives Into the Csf And Brain Tissuementioning

confidence: 99%

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

2010

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SUMMARY The entry of anti-infectives into the central nervous system (CNS) depends on the compartment studied, molecular size, electric charge, lipophilicity, plasma protein binding, affinity to active transport systems at the blood-brain/blood-cerebrospinal fluid (CSF) barrier, and host factors such as meningeal inflammation and CSF flow. Since concentrations in microdialysates and abscesses are not frequently available for humans, this review focuses on drug CSF concentrations. The ideal compound to treat CNS infections is of small molecular size, is moderately lipophilic, has a low level of plasma protein binding, has a volume of distribution of around 1 liter/kg, and is not a strong ligand of an efflux pump at the blood-brain or blood-CSF barrier. When several equally active compounds are available, a drug which comes close to these physicochemical and pharmacokinetic properties should be preferred. Several anti-infectives (e.g., isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones) reach a CSF-to-serum ratio of the areas under the curves close to 1.0 and, therefore, are extremely valuable for the treatment of CNS infections. In many cases, however, pharmacokinetics have to be balanced against in vitro activity. Direct injection of drugs, which do not readily penetrate into the CNS, into the ventricular or lumbar CSF is indicated when other effective therapeutic options are unavailable.

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Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis

Cited by 91 publications

References 79 publications

Sepsis-Associated Encephalopathy: A Magnetic Resonance Imaging and Spectroscopy Study

Sepsis-Associated Encephalopathy: A Magnetic Resonance Imaging and Spectroscopy Study

The neuroinflammatory hypothesis of delirium

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

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