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Low-molecular-weight polyethylene glycol improves survival in experimental sepsis

Ackland, GL; Del Arroyo, AG; Yao, ST; Stephens, RC; Dyson, A; Klein, NJ; ... Gourine, AV; + view all (2010) Low-molecular-weight polyethylene glycol improves survival in experimental sepsis. CRIT CARE MED , 38 (2) 629 - 636. 10.1097/CCM.0b013e3181c8fcd0.

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Abstract

Objective: For several chronic inflammatory disease states, therapy is enhanced by improving the pharmacokinetic properties of anti-inflammatory drugs through conjugation with polyethylene glycol. We hypothesized that part of the beneficial action of PEGylated drugs may be derived from the anti-inflammatory properties of polyethylene glycol (PEG) itself.Design: Randomized, double-blinded, controlled ex vivo and in vivo laboratory studies.Setting: University research laboratories.Subjects: Human neutrophils and mononuclear cells, macrophage cell line, and adult rats and mice.Interventions: The effect of PEG (either low-molecular-weight [200-400] or high-molecular-weight [>4000]) was assessed on survival after systemic inflammation induced by lipopolysaccharide or zymosan. The effects of PEG on zymosan, lipopolysaccharide, or streptolysin-induced inflammatory and bioenergetic responses of immune cells were also assessed.Measurements and Main Results: Low-molecular-weight PEG reduced inflammatory cytokine expression, pyrexia, and mortality by >50% in both lipopolysaccharide and zymosan models of sepsis. Low-molecular-weight PEG reduced cytokine expression both in vivo and in vitro, and attenuated activation of human neutrophils in response to lipopolysaccharide or zymosan. By contrast, high-molecular-weight PEG conferred less significant survival effects after lipopolysaccharide and zymosan, and it did not exhibit such profound anti-inflammatory effects. Low-molecular-weight PEG attenuated lipopolysaccharide-induced activation of pro-apoptotic pathways (lysophosphatidic acid receptor and caspase-domain signaling) in the livers of endotoxemic rats.Streptolysin-induced necrosis of human neutrophils was reduced by low-molecular-weight PEG, indicating a mechanism that involves coating and/or stabilizing the cellular membrane. Low-molecular-weight PEG preserved human neutrophil responses to septic serum and bioenergetic function in macrophages and neutrophils.Conclusion: PEG is a commonly used, safe, nonimmunogenic molecule possessing hitherto unappreciated anti-inflammatory properties. Low-molecular-weight PEG may potentially play a role in the therapy of systemic inflammation and sepsis. (Crit Care Med 2010; 38:629-636)

Type:Article
Title:Low-molecular-weight polyethylene glycol improves survival in experimental sepsis
DOI:10.1097/CCM.0b013e3181c8fcd0
Keywords:polyethylene glycol, sepsis, neutrophil, cell membrane structure, SPINAL-CORD-INJURY, NF-KAPPA-B, NITRIC-OXIDE, LYSOPHOSPHATIDIC ACID, ISCHEMIA-REPERFUSION, ORGAN DYSFUNCTION, URINARY-EXCRETION, HEMORRHAGIC-SHOCK, PORE FORMATION, SEPTIC SHOCK
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Neuroscience, Physiology and Pharmacology
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Clinical Physiology

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