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Host Defense Peptides of Thrombin Modulate Inflammation and Coagulation in Endotoxin-Mediated Shock and Pseudomonas aeruginosa Sepsis.

Kalle, Martina LU ; Papareddy, Praveen LU ; Kasetty, Gopinath LU ; Mörgelin, Matthias LU ; van der Plas, Mariena LU ; Rydengård, Victoria LU ; Malmsten, Martin; Albiger, Barbara LU and Schmidtchen, Artur LU (2012) In PLoS One 7(12).
Abstract
Gram-negative sepsis is accompanied by a disproportionate innate immune response and excessive coagulation mainly induced by endotoxins released from bacteria. Due to rising antibiotic resistance and current lack of other effective treatments there is an urgent need for new therapies. We here present a new treatment concept for sepsis and endotoxin-mediated shock, based on host defense peptides from the C-terminal part of human thrombin, found to have a broad and inhibitory effect on multiple sepsis pathologies. Thus, the peptides abrogate pro-inflammatory cytokine responses to endotoxin in vitro and in vivo. Furthermore, they interfere with coagulation by modulating contact activation and tissue factor-mediated clotting in vitro, leading... (More)
Gram-negative sepsis is accompanied by a disproportionate innate immune response and excessive coagulation mainly induced by endotoxins released from bacteria. Due to rising antibiotic resistance and current lack of other effective treatments there is an urgent need for new therapies. We here present a new treatment concept for sepsis and endotoxin-mediated shock, based on host defense peptides from the C-terminal part of human thrombin, found to have a broad and inhibitory effect on multiple sepsis pathologies. Thus, the peptides abrogate pro-inflammatory cytokine responses to endotoxin in vitro and in vivo. Furthermore, they interfere with coagulation by modulating contact activation and tissue factor-mediated clotting in vitro, leading to normalization of coagulation responses in vivo, a previously unknown function of host defense peptides. In a mouse model of Pseudomonas aeruginosa sepsis, the peptide GKY25, while mediating a modest antimicrobial effect, significantly inhibited the pro-inflammatory response, decreased fibrin deposition and leakage in the lungs, as well as reduced mortality. Taken together, the capacity of such thrombin-derived peptides to simultaneously modulate bacterial levels, pro-inflammatory responses, and coagulation, renders them attractive therapeutic candidates for the treatment of invasive infections and sepsis. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
PLoS One
volume
7
issue
12
publisher
Public Library of Science
external identifiers
  • WOS:000312386600022
  • PMID:23272096
  • Scopus:84871268218
ISSN
1932-6203
DOI
10.1371/journal.pone.0051313
language
English
LU publication?
yes
id
b7eec085-a12e-4d67-8819-31f23129fbb5 (old id 3346872)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23272096?dopt=Abstract
date added to LUP
2013-01-02 12:40:04
date last changed
2016-10-13 04:32:45
@misc{b7eec085-a12e-4d67-8819-31f23129fbb5,
  abstract     = {Gram-negative sepsis is accompanied by a disproportionate innate immune response and excessive coagulation mainly induced by endotoxins released from bacteria. Due to rising antibiotic resistance and current lack of other effective treatments there is an urgent need for new therapies. We here present a new treatment concept for sepsis and endotoxin-mediated shock, based on host defense peptides from the C-terminal part of human thrombin, found to have a broad and inhibitory effect on multiple sepsis pathologies. Thus, the peptides abrogate pro-inflammatory cytokine responses to endotoxin in vitro and in vivo. Furthermore, they interfere with coagulation by modulating contact activation and tissue factor-mediated clotting in vitro, leading to normalization of coagulation responses in vivo, a previously unknown function of host defense peptides. In a mouse model of Pseudomonas aeruginosa sepsis, the peptide GKY25, while mediating a modest antimicrobial effect, significantly inhibited the pro-inflammatory response, decreased fibrin deposition and leakage in the lungs, as well as reduced mortality. Taken together, the capacity of such thrombin-derived peptides to simultaneously modulate bacterial levels, pro-inflammatory responses, and coagulation, renders them attractive therapeutic candidates for the treatment of invasive infections and sepsis.},
  author       = {Kalle, Martina and Papareddy, Praveen and Kasetty, Gopinath and Mörgelin, Matthias and van der Plas, Mariena and Rydengård, Victoria and Malmsten, Martin and Albiger, Barbara and Schmidtchen, Artur},
  issn         = {1932-6203},
  language     = {eng},
  number       = {12},
  publisher    = {ARRAY(0x8b6d1c8)},
  series       = {PLoS One},
  title        = {Host Defense Peptides of Thrombin Modulate Inflammation and Coagulation in Endotoxin-Mediated Shock and Pseudomonas aeruginosa Sepsis.},
  url          = {http://dx.doi.org/10.1371/journal.pone.0051313},
  volume       = {7},
  year         = {2012},
}