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

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.

• Authors: Gareth L Ackland, Ana Gutierrez Del Arroyo, Song T Yao, Robert C Stephens, Alexander Dyson, Nigel J Klein, Mervyn Singer, Alexander V Gourine
• Journal: Critical care medicine (Crit Care Med) Vol. 38 Issue 2 Pg. 629-36 (Feb 2010) ISSN: 1530-0293 [Electronic] United States
• PMID: 20009757 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Polyethylene Glycols

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Cell Line
• Cell Survival (drug effects)
• Cytokines (biosynthesis)
• Female
• Flow Cytometry
• Humans
• Inflammation (drug therapy)
• Leukocytes, Mononuclear (drug effects)
• Macrophages (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Neutrophils (drug effects)
• Polyethylene Glycols (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Sepsis (drug therapy)
• Stroke Volume (drug effects)