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J. Biol. Chem., Vol. 277, Issue 16, 14274-14280, April 19, 2002
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From the Departments of Gram-negative bacterial sepsis commonly causes
organ dysfunction and death in humans. Although circulating bacterial
toxins trigger inflammation in sepsis, little is known about the
composition of bacterial products released into the blood during
sepsis or the contribution of various bacterial components to the
pathogenesis of sepsis. We have shown that diverse Gram-negative
bacteria release bacterial peptidoglycan-associated lipoprotein (PAL)
into serum. The present studies explored release of PAL into the blood
during sepsis and tested the hypothesis that PAL contributes to
bacterial virulence and inflammation in Gram-negative sepsis. Released
PAL was detected in the blood of 94% of mice following cecal ligation and puncture. Picomolar to nanomolar levels of PAL stimulated macrophages and splenocytes from lipopolysaccharide-hyporesponsive (C3H/HeJ) mice. Injection of PAL into C3H/HeJ mice stimulated production of serum cytokines and increased pulmonary and myocardial expression of inflammatory markers. PAL caused death in sensitized C3H/HeJ mice. Mutant Escherichia coli bacteria with reduced
levels of PAL or truncated PAL were less virulent than wild-type
bacteria, as indicated by higher survival rates and lower circulating
levels of interleukin 6 and bacteria in a model of peritonitis in
lipopolysaccharide-responsive mice. The studies suggest that PAL
may be an important bacterial mediator of Gram-negative sepsis.
Bacterial Peptidoglycan-associated Lipoprotein Is Released into
the Bloodstream in Gram-negative Sepsis and Causes Inflammation and
Death in Mice*
§,¶,,
, and**
Anesthesia and Critical Care,
¶ Pediatrics, and ** Medicine and Infectious
Disease Unit, Massachusetts General Hospital and Harvard Medical
School, Charlestown, Massachusetts 02129
*
This work was supported by grants from the Harvard Medical
School Scholars in Medicine Program (to J. H.) and the Hood Foundation (to J. H.) and by National Institutes of Health Grants AI01722 (to
J. H.) GM59694 (to J. H. and H. S. W.), and HL-04237 (to
J. D. R.). Patent applications related to PAL have been filed by J. H. and H. S. W.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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