Pete Lollar, MD
2010-03-01
Dr. Lollar indicated no relevant conflicts of interest.
Xu J, Zhang X, Pelayo R, et al. Extracellular
histones are major mediators of death in sepsis.
Nat Med. 2009;15:1318-21.
The relationship between hemostasis and inflammation has
emerged as a major area of investigation in recent years. The
laboratory of Charles Esmon, in which the present work was
performed, has played a major role in developing this area of study by
unraveling mechanisms by which the serine protease, activated protein
C (APC), functions. This effort led to the discovery by Esmon and
Fletcher Taylor, a co-author of this paper, of APC as a potential therapeutic
agent in the treatment of sepsis. Consequently, a recombinant
APC product (drotrecogin alfa [activated]) was approved by the Food
and Drug Administration in 2001 as the first treatment for adult patients
with severe sepsis who are at high risk for death.
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Several possible mechanisms have been identified to explain the anti-inflammatory
functions of APC. The current study originated from the
suspicion that the list of potential mediators of sepsis that are targeted
by APC may be incomplete. To search for additional candidates, the
authors exposed cultured endothelial cells to products released by
a lipopolysaccharide- and interferon-γ-activated murine macrophage
cell line. The releasate from these cells was cytotoxic toward the endothelial
cells and addition of
APC reduced the cytotoxicity.
This finding instigated a
hunt for putative substrates
in the releasate that are
targets for proteolytic degradation
by APC and led to
the identification of three
small proteins with apparent
molecular masses of
10, 13, and 15 kDa. Amino
acid sequencing identified
them as histones H4, H3,
and H2A. Experiments using
purified histone proteins
confirmed that they are proteolytic
substrates for APC
and that cleavage decreases
their cytotoxicity. Subsequent experiments revealed that that purified
histones are cytotoxic toward endothelium in vitro and are lethal in
mice. Anti-histone antibodies reduced the mortality in three models of
murine sepsis. Additionally, histones were detected in the circulation of
baboons subjected to Escherichia coli-induced sepsis. Co-infusion of
APC with E. coli reduced mortality in baboons or mice. Finally, elevated
histone levels were identified in the plasma of septic human patients,
and cleaved H3 was observed in the plasma of one patient.
Histones are nuclear proteins that bind DNA and form nucleosomes,
which are the primary components of chromatin. What are they doing
outside of cells, and where do they come from? The findings in the
present study are consistent with the identification of so-called neutrophil
extracellular traps (NETs), which are partly made up of chromatin
and are produced during sepsis, possibly to trap infectious agents.1
This study provides compelling evidence that histones are primary mediators
of sepsis and not merely a by-product. As noted by the authors,
these results suggest new therapeutic approaches in the treatment
of sepsis, such as the use of anti-histone antibodies or other histone
blockers that could circumvent the bleeding complications that can result
from APC therapy.
- Clark SR, Ma AC, Tavener SA, et al. Platelet
TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic
blood. Nat Med. 2007;13:463-69.
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