Abstract
Hemoadsorption devices are used to treat septic shock by adsorbing inflammatory cytokines and as yet incompletely defined danger and pathogen associated molecular patterns. In an ideal case, hemoadsorption results in immediate recovery of microvascular endothelial cells’ (mEC) function and rapid recovery from catecholamine-dependency and septic shock. We here tested a single device, which consists of polystyrene-divinylbenzene core particles of 450 μm diameter with a high affinity for hydrophobic compounds. The current study aimed at the proof of concept that endothelial-specific damage mediators are adsorbed and can be recovered from hemoadsorption devices. Because of excellent clinical experience, we tested protein fractions released from a hemoadsorber in a novel endothelial bioassay. Video-based, long-term imaging of mEC proliferation and cell death were evaluated and combined with apoptosis and ATP measurements. Out of a total of 39 fractions recovered from column fractionation, we identified 3 fractions that caused i) inhibition of mEC proliferation, ii) increased cell death and iii) induction of apoptosis in mEC. When adding these 3 fractions to mEC, their ATP contents were reduced. These fractions contained proteins of approximately 15 kDa, and high amounts of nucleic acid, which was at least in part oxidized. The efficacy for endothelial cell damage prevention by hemoadsorption can be addressed by a novel endothelial bioassay and long-term video observation procedures. Protein fractionation of the hemoadsorption devices used is feasible to study and define endothelial damage ligands on a molecular level. The results suggest a significant effect by circulating nucleic acids – bound to an as yet undefined protein, which may constitute a major danger-associated molecular pattern (DAMP) in the exacerbation of inflammation when patients experience septic shock. Hemoadsorption devices may thus limit endothelial damage, through the binding of nucleic acid-bearing aggregates and thus contribute to improved endothelial barrier function.
Highlights
To date, the complexity of pathologies in septic shock may explain why therapeutic approaches targeting a specific mediator have largely failed
Despite the likelihood of such complicated molecular networks in driving organ failure in sepsis and septic shock, we here attempted to identify protein fractions retrieved by CytoSorb adsorption that lead to endothelial damage in the absence of white blood cells
Despite the likely involvement of multiple mediators in the pathology of septic shock, with a molecular weight ranging between 10–60 kDa, which may explain the experimental and clinical evidence for the resolution of septic shock by this hemoadsorption device[7,9,25], we here approached the identification and enrichment of defined protein fractions based on their capacity to influence endothelial cell viability
Summary
The complexity of pathologies in septic shock may explain why therapeutic approaches targeting a specific mediator have largely failed. Www.nature.com/scientificreports evidence that organ damage requires a panel of mediators and the same may be true for tissue regeneration and reconstitution This may be one reason for the failure of a multitude of clinical trials in sepsis and septic shock where only selected mediators where targeted[23]. Despite the likelihood of such complicated molecular networks in driving organ failure in sepsis and septic shock, we here attempted to identify protein fractions retrieved by CytoSorb adsorption that lead to endothelial damage in the absence of white blood cells. Despite the likely involvement of multiple mediators in the pathology of septic shock, with a molecular weight ranging between 10–60 kDa, which may explain the experimental and clinical evidence for the resolution of septic shock by this hemoadsorption device[7,9,25], we here approached the identification and enrichment of defined protein fractions based on their capacity to influence endothelial cell viability. The active fractions are ready for further characterization to stratify patients into groups which could possibly benefit from hemoadsorption therapy
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