Back to Search
Start Over
Low-molecular-weight polyethylene glycol improves survival in experimental sepsis*
- Source :
- Critical Care Medicine. 38:629-636
- Publication Year :
- 2010
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2010.
-
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)
- Subjects :
- Male
Lipopolysaccharide
Cell Survival
Neutrophils
Anti-Inflammatory Agents
Polyethylene glycol
Pharmacology
Critical Care and Intensive Care Medicine
Cell Line
Polyethylene Glycols
Sepsis
Mice
chemistry.chemical_compound
In vivo
Intensive care
PEG ratio
medicine
Animals
Humans
Rats, Wistar
Inflammation
business.industry
Macrophages
Zymosan
Stroke Volume
Flow Cytometry
medicine.disease
Rats
Mice, Inbred C57BL
chemistry
Immunology
Leukocytes, Mononuclear
Cytokines
Female
business
Ex vivo
Subjects
Details
- ISSN :
- 00903493
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Critical Care Medicine
- Accession number :
- edsair.doi.dedup.....9680c57bd6e83d577d968470d2cbbf4b