Host defense peptides of thrombin modulate inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis
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Host defense peptides of thrombin modulate inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis. / Kalle, Martina; Papareddy, Praveen; Kasetty, Gopinath; Mörgelin, Matthias; van der Plas, Mariena J A; Rydengård, Victoria; Malmsten, Martin; Albiger, Barbara; Schmidtchen, Artur.
In: PLOS ONE, Vol. 7, No. 12, 2012, p. e51313.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Host defense peptides of thrombin modulate inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis
AU - Kalle, Martina
AU - Papareddy, Praveen
AU - Kasetty, Gopinath
AU - Mörgelin, Matthias
AU - van der Plas, Mariena J A
AU - Rydengård, Victoria
AU - Malmsten, Martin
AU - Albiger, Barbara
AU - Schmidtchen, Artur
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Blood Coagulation
KW - Cytokines
KW - Disease Models, Animal
KW - Endotoxins
KW - Escherichia coli
KW - Fibrin
KW - Flow Cytometry
KW - Humans
KW - Inflammation
KW - Lipopolysaccharides
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Microscopy, Electron, Scanning
KW - Peptides
KW - Pseudomonas aeruginosa
KW - Sepsis
KW - Shock, Septic
KW - Thrombin
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1371/journal.pone.0051313
DO - 10.1371/journal.pone.0051313
M3 - Journal article
C2 - 23272096
VL - 7
SP - e51313
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 12
ER -
ID: 186451136