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.