title: Host defense peptides of thrombin modulate inflammation and coagulation in endotoxin-mediated shock and Pseudomonas aeruginosa sepsis.
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.
authors.affiliation: Division of Dermatology and Venereology, Department of Clinical Sciences, Biomedical Center, Lund University, Lund, Sweden. martina.kalle@med.lu.se
authors.forename: Martina
authors.initials: M
authors.lastname: Kalle
authors.forename: Praveen
authors.initials: P
authors.lastname: Papareddy
authors.forename: Gopinath
authors.initials: G
authors.lastname: Kasetty
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Mariena J A
authors.initials: MJ
authors.lastname: van der Plas
authors.forename: Victoria
authors.initials: V
authors.lastname: Rydengård
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
authors.forename: Barbara
authors.initials: B
authors.lastname: Albiger
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004731:Endotoxins / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D005337:Fibrin / Q000737:chemistry; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning / Q000379:methods; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D018805:Sepsis; D012772:Shock, Septic / Q000378:metabolism*; D013917:Thrombin / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D010455:Peptides; D005337:Fibrin; D013917:Thrombin