Host Defense Peptides of Thrombin Modulate Inflammation and Coagulation in Endotoxin-Mediated Shock and Pseudomonas aeruginosa Sepsis.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3346872
- author
- Kalle, Martina LU ; Papareddy, Praveen LU ; Kasetty, Gopinath LU ; Mörgelin, Matthias LU ; van der Plas, Mariena LU ; Rydengård, Victoria LU ; Malmsten, Martin LU ; Albiger, Barbara LU and Schmidtchen, Artur LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 7
- issue
- 12
- article number
- e51313
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000312386600022
- pmid:23272096
- scopus:84871268218
- pmid:23272096
- 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
- 2016-04-04 09:33:20
- date last changed
- 2022-03-15 19:51:42
@article{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 = {{Public Library of Science (PLoS)}}, series = {{PLoS ONE}}, title = {{Host Defense Peptides of Thrombin Modulate Inflammation and Coagulation in Endotoxin-Mediated Shock and Pseudomonas aeruginosa Sepsis.}}, url = {{https://lup.lub.lu.se/search/files/5355570/3526831.pdf}}, doi = {{10.1371/journal.pone.0051313}}, volume = {{7}}, year = {{2012}}, }