Loading…
Polymyxin B-Conjugated α2-Macroglobulin as an Adjunctive Therapy to Sepsis: Modes of Action and Impact on Lethality
A drug targeting both the inflammatory initiators (lipopolysaccharide; LPS) and mediators [tumor necrosis factor-α (TNF-α)] should have advantage over a âsingle-factor targeting strategyâ in sepsis prevention trials. We have prepared conjugates of polymyxin B (PMB) and the cytokine binding pro...
Saved in:
Published in: | The Journal of pharmacology and experimental therapeutics 2006-08, Vol.318 (2), p.762 |
---|---|
Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | A drug targeting both the inflammatory initiators (lipopolysaccharide; LPS) and mediators [tumor necrosis factor-α (TNF-α)]
should have advantage over a âsingle-factor targeting strategyâ in sepsis prevention trials. We have prepared conjugates of
polymyxin B (PMB) and the cytokine binding protein α2-macroglobulin (A2M). The conjugate binds TNF-α as well as LPS as studied
by electrophoresis and phase partitioning. Compared with free PMB, the conjugate is nontoxic to cells and does not affect
the viability of human monocytes. The A2M-PMB conjugate binds to the A2M receptor (CD91/low-density lipoprotein receptor-related
protein 1) with affinity similar to that of the nonmodified protein. Fluorescein isothiocyanate-labeled LPS in the presence
of A2M-PMB is rapidly transported into fibroblasts for degradation via receptor-mediated endocytosis. In vitro, A2M-PMB demonstrated
inhibition of LPS-induced secretion of TNF-α from isolated monocytes as well as in the whole blood assay. The efficacy of
the drug was tested in mice after induction of acute inflammation (LPS model) and after induction of a polymicrobial sepsis
by cecal ligation and puncture (CLP) model. Treatment of mice with A2M-PMB up to 250 μg/g body weight was not toxic to the
animal. When the drug was administered 30 min before or 30 min after the LPS challenge, a survival rate of 90 and 70%, respectively,
was obtained compared with the placebo control group (5%). A2M-PMB also protected mice after induction of polymicrobial sepsis
when administered 30 min before CLP. These results support our hypothesis that A2M-PMB acts as a polyvalent drug to target
different host mediators as well as sepsis inducer at the same time. |
---|---|
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.106.104265 |