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New strategies for treatment of infectious sepsis
- Source :
- Journal of leukocyte biology. 106(1)
- Publication Year :
- 2018
-
Abstract
- In this mini review, we describe the molecular mechanisms in polymicrobial sepsis that lead to a series of adverse events including activation of inflammatory and prothrombotic pathways, a faulty innate immune system, and multiorgan dysfunction. Complement activation is a well-established feature of sepsis, especially involving generation of C5a and C5b-9, along with engagement of relevant receptors for C5a. Activation of neutrophils by C5a leads to extrusion of DNA, forming neutrophil extracellular traps that contain myeloperoxidase and oxidases, along with extracellular histones. Generation of the distal complement activation product, C5b-9 (known as the membrane attack complex, MAC), also occurs in sepsis. C5b-9 activates the NLRP3 inflammasome, which damages mitochondria, together with appearance in plasma of IL-1β and IL-18. Histones are strongly proinflammatory as well as being prothrombotic, leading to activation of platelets and development of venous thrombosis. Multiorgan dysfunction is also a feature of sepsis. It is well known that septic cardiomyopathy, which if severe, can lead to death. This complication in sepsis is linked to reduced levels in cardiomyocytes of three critical proteins (SERCA2, NCX, Na+/K+-ATPase). The reductions in these three key proteins are complement- and histone-dependent. Dysfunction of these ATPases is linked to the cardiomyopathy of sepsis. These data suggest novel targets in the setting of sepsis in humans.
- Subjects :
- 0301 basic medicine
Immunology
Complement receptor
Complement Membrane Attack Complex
Biology
Communicable Diseases
Proinflammatory cytokine
Sepsis
Histones
03 medical and health sciences
0302 clinical medicine
NLR Family, Pyrin Domain-Containing 3 Protein
medicine
Immunology and Allergy
Animals
Humans
Innate immune system
Inflammasome
Cell Biology
Neutrophil extracellular traps
Complement System Proteins
medicine.disease
Complement system
030104 developmental biology
030220 oncology & carcinogenesis
Complement membrane attack complex
Cardiomyopathies
medicine.drug
Subjects
Details
- ISSN :
- 19383673
- Volume :
- 106
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of leukocyte biology
- Accession number :
- edsair.doi.dedup.....bea8828f1337413a47d33b91fc64f59f