Host defense peptides of thrombin modulate inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis

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 - 2012/12/13

Y1 - 2012/12/13

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

SN - 1932-6203

VL - 7

SP - e51313

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 12

ER -