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Kininogen supports inflammation and bacterial spreading during Streptococccus Pyogenes Sepsis.

ABSTRACT: BACKGROUND:High-molecular-weight kininogen is a cofactor of the human contact system, an inflammatory response mechanism that is activated during sepsis. It has been shown that high-molecular-weight kininogen contributes to endotoxemia, but is not critical for local host defense during pneumonia by Gram-negative bacteria. However, some important pathogens, such as Streptococcus pyogenes, can cleave kininogen by contact system activation. Whether kininogen causally affects antibacterial host defense in S. pyogenes infection, remains unknown. METHODS:Kininogen concentration was determined in course plasma samples from septic patients. mRNA expression and degradation of kininogen was determined in liver or plasma of septic mice. Kininogen was depleted in mice by treatment with selective kininogen directed antisense oligonucleotides (ASOs) or a scrambled control ASO for 3 weeks prior to infection. 24 h after infection, infection parameters were determined. FINDINGS:Data from human and mice samples indicate that kininogen is a positive acute phase protein. Lower kininogen concentration in plasma correlate with a higher APACHE II score in septic patients. We show that ASO-mediated depletion of kininogen in mice indeed restrains streptococcal spreading, reduces levels of proinflammatory cytokines such as IL-1? and IFN?, but increased intravascular tissue factor and fibrin deposition in kidneys of septic animals. INTERPRETATION:Mechanistically, kininogen depletion results in reduced plasma kallikrein levels and, during sepsis, in increased intravascular tissue factor that may reinforce immunothrombosis, and thus reduce streptococcal spreading. These novel findings point to an anticoagulant and profibrinolytic role of kininogens during streptococcal sepsis. FUNDING:Full details are provided in the Acknowledgements section.

SUBMITTER: Kohler J

PROVIDER: S-EPMC7381504 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Kininogen supports inflammation and bacterial spreading during Streptococccus Pyogenes Sepsis.

Köhler Juliane J Maletzki Claudia C Koczan Dirk D Frank Marcus M Springer Armin A Steffen Carolin C Revenko Alexey S AS MacLeod A Robert AR Mikkat Stefan S Kreikemeyer Bernd B Oehmcke-Hecht Sonja S

EBioMedicine 20200721

<h4>Background</h4>High-molecular-weight kininogen is a cofactor of the human contact system, an inflammatory response mechanism that is activated during sepsis. It has been shown that high-molecular-weight kininogen contributes to endotoxemia, but is not critical for local host defense during pneumonia by Gram-negative bacteria. However, some important pathogens, such as Streptococcus pyogenes, can cleave kininogen by contact system activation. Whether kininogen causally affects antibacterial h ...[more]

PMID: 32707450

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Project description:Sepsis is characterized by a life-threatening organ dysfunction caused by an unbalanced host response to microbe infection that can lead to death. Besides being currently the leading cause of death in intensive care units worldwide, sepsis can also induce long-term consequences among survivors, such as cognitive impairment. Statins (lipid-lowering drugs widely used to treat dyslipidemia) have been shown to possess pleiotropic anti-inflammatory and antimicrobial effects. These drugs act inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the limiting step in cholesterol biosynthesis. In this work, we evaluated the therapeutic effects of simvastatin in an animal model of sepsis. In previous study from our group, statin pretreatment avoided cognitive damage and neuroinflammation in sepsis survivors. Herein, we focused on acute inflammation where sepsis was induced by cecal ligation and puncture (CLP), and the animals were treated with simvastatin (2 mg/kg) 6 h after surgery. We measured plasma biochemical markers of organ dysfunction, cell migration, cell activation, bacterial elimination, production of nitric oxide 24 h after CLP, survival rate for 7 days, and cognitive impairment 15 days after CLP. One single administration of simvastatin 6 h after CLP was able to prevent both liver and kidney dysfunction. In addition, this drug decreased cell accumulation in the peritoneum as well as the levels of TNF-α, MIF, IL-6, and IL-1β. Simvastatin diminished the number of bacterial colony forming units (CFU) and increased the production of nitric oxide production in the peritoneum. Simvastatin treatment increased survival for the first 24 h, but it did not alter survival rate at the end of 7 days. Our results showed that posttreatment with simvastatin hampered organ dysfunction, increased local production of nitric oxide, improved bacterial clearance, and modulated inflammation in a relevant model of sepsis.

Dataset Information

Kininogen supports inflammation and bacterial spreading during Streptococccus Pyogenes Sepsis.

Publications

Kininogen supports inflammation and bacterial spreading during Streptococccus Pyogenes Sepsis.

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