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Host response in sepsis

Berkestedt, Ingrid LU (2009) In Lund University Faculty of Medicine Doctoral Dissertation Series 2009:46.
Abstract
Sepsis is a serious condition characterized by a systemic inflammatory response to an infection. Increased vascular leakage, vasodilation and heart failure cause circulatory disturbances challenging the intensivist. Despite modern medication and high technology supportive care, mortality is high. Key strategies include to find and take care of causative agents at the infection site. Unfortunately, the microbes are sometimes “slippery small ones” protecting themselves by for example resistance against antibiotics. But our body is amazing! For example cells, such as neutrophil granulocytes, produce antibiotic substances (antimicrobial peptides, AMPs). Increased knowledge of the host response in sepsis will aid in refining and developing new... (More)
Sepsis is a serious condition characterized by a systemic inflammatory response to an infection. Increased vascular leakage, vasodilation and heart failure cause circulatory disturbances challenging the intensivist. Despite modern medication and high technology supportive care, mortality is high. Key strategies include to find and take care of causative agents at the infection site. Unfortunately, the microbes are sometimes “slippery small ones” protecting themselves by for example resistance against antibiotics. But our body is amazing! For example cells, such as neutrophil granulocytes, produce antibiotic substances (antimicrobial peptides, AMPs). Increased knowledge of the host response in sepsis will aid in refining and developing new treatment.



We investigated the effect of the AMP, LL-37, on smooth muscle activity in isolated human omental vessels and found that it causes formyl peptide receptor-like 1 mediated dilation in the veins mainly via action of endothelium-derived hyperpolarizing factor.



Earlier studies have shown that increased levels of glycosaminoglycans (GAGs) inhibit the action of AMPs in chronic wounds. We found increased plasma levels of GAGs in sepsis patients correlating to mortality and level of circulatory derangement. GAGs at concentrations relevant to sepsis patients inhibited the antimicrobial action of AMPs in vitro.



Plasma levels of AMPs were generally higher in sepsis patients than in controls and correlated to inflammatory activation, circulatory derangement and neutrophil activity.



Finally, we found that the contact system is activated in patients with severe sepsis reflected by decreased levels of high-molecular-weight kininogen. The levels of the main effector, bradykinin, were, however, also decreased, suggesting substrate depletion in the state of established severe sepsis. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Sigurdsson, Gisli H, Department of Aneasthesiology and Intensive Care Medicine, Landspitali University Hospital, Reykjavik, Iceland
organization
publishing date
type
Thesis
publication status
published
subject
keywords
severe sepsis, contact system, glycosaminoglycan, antimicrobial peptide, human
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2009:46
pages
105 pages
publisher
Avd för anestesiologi och intensivvård
defense location
Segerfalkssalen, Wallenberg neurocentrum, Lund
defense date
2009-05-19 09:15:00
external identifiers
  • scopus:68949083424
ISSN
1652-8220
ISBN
978-91-86253-34-9
language
English
LU publication?
yes
id
8ed010ef-ce69-441a-a2e7-41b6ca698c13 (old id 1389989)
date added to LUP
2016-04-01 14:04:46
date last changed
2023-04-18 20:22:42
@phdthesis{8ed010ef-ce69-441a-a2e7-41b6ca698c13,
  abstract     = {{Sepsis is a serious condition characterized by a systemic inflammatory response to an infection. Increased vascular leakage, vasodilation and heart failure cause circulatory disturbances challenging the intensivist. Despite modern medication and high technology supportive care, mortality is high. Key strategies include to find and take care of causative agents at the infection site. Unfortunately, the microbes are sometimes “slippery small ones” protecting themselves by for example resistance against antibiotics. But our body is amazing! For example cells, such as neutrophil granulocytes, produce antibiotic substances (antimicrobial peptides, AMPs). Increased knowledge of the host response in sepsis will aid in refining and developing new treatment.<br/><br>
<br/><br>
We investigated the effect of the AMP, LL-37, on smooth muscle activity in isolated human omental vessels and found that it causes formyl peptide receptor-like 1 mediated dilation in the veins mainly via action of endothelium-derived hyperpolarizing factor.<br/><br>
<br/><br>
Earlier studies have shown that increased levels of glycosaminoglycans (GAGs) inhibit the action of AMPs in chronic wounds. We found increased plasma levels of GAGs in sepsis patients correlating to mortality and level of circulatory derangement. GAGs at concentrations relevant to sepsis patients inhibited the antimicrobial action of AMPs in vitro.<br/><br>
<br/><br>
Plasma levels of AMPs were generally higher in sepsis patients than in controls and correlated to inflammatory activation, circulatory derangement and neutrophil activity.<br/><br>
<br/><br>
Finally, we found that the contact system is activated in patients with severe sepsis reflected by decreased levels of high-molecular-weight kininogen. The levels of the main effector, bradykinin, were, however, also decreased, suggesting substrate depletion in the state of established severe sepsis.}},
  author       = {{Berkestedt, Ingrid}},
  isbn         = {{978-91-86253-34-9}},
  issn         = {{1652-8220}},
  keywords     = {{severe sepsis; contact system; glycosaminoglycan; antimicrobial peptide; human}},
  language     = {{eng}},
  publisher    = {{Avd för anestesiologi och intensivvård}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Host response in sepsis}},
  url          = {{https://lup.lub.lu.se/search/files/3764080/1390010.pdf}},
  volume       = {{2009:46}},
  year         = {{2009}},
}