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The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a...
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Updated: Nov 22, 2025

Evaluation of a Reliable Biomarker in a Cecal Ligation and Puncture-Induced Mouse Model of Sepsis
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Role of Complement and Histones in Sepsis.

Firas S Zetoune1, Peter A Ward1

  • 1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, United States.

Frontiers in Medicine
|January 11, 2021
PubMed
Summary

Sepsis research shows complement activation product C5a drives harmful extracellular histones, leading to organ damage. Blocking C5a significantly improves survival rates in sepsis models, offering a potential therapeutic strategy.

Keywords:
C5aC5b-9METsNETsNLRP3 inflammasomeROSanaphylatoxinshistones

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Area of Science:

  • Immunology
  • Pathophysiology
  • Pharmacology

Background:

  • Sepsis remains a leading cause of mortality with no specific FDA-approved treatments despite numerous clinical trials.
  • The mouse model of polymicrobial sepsis is crucial for understanding human sepsis pathophysiology.
  • Adverse effects of sepsis involve complement activation products, particularly C5a anaphylatoxin and its receptors.

Purpose of the Study:

  • To investigate the role of complement activation products, specifically C5a, in sepsis-induced organ dysfunction.
  • To elucidate the relationship between C5a, extracellular histones, and sepsis progression.
  • To evaluate therapeutic strategies targeting C5a for sepsis treatment.

Main Methods:

  • Utilized a mouse model of polymicrobial sepsis.
  • Monitored complement activation products (C5a) and extracellular histones in plasma.
  • Assessed the impact of C5a and its receptors (C5aR1, C5aR2) on cell injury and organ dysfunction.
  • Investigated the effects of C5a neutralization via antibody and C5aR1 absence on sepsis outcomes.
  • Evaluated survival rates in septic mice.

Main Results:

  • C5a appearance in sepsis correlates with extracellular histone presence in plasma.
  • Extracellular histones exhibit potent pro-inflammatory and pro-thrombotic activities, causing cell injury and multiorgan dysfunction.
  • Sepsis-induced cardiomyopathy is dependent on C5a, its receptors, and histones.
  • Neutralization of C5a or absence of C5aR1 prevents extracellular histone appearance and mitigates cell and organ failure.
  • Blockade of C5a with antibodies significantly improves survival rates in septic mice.

Conclusions:

  • C5a plays a critical role in sepsis pathogenesis by promoting the release and activity of extracellular histones.
  • Targeting C5a represents a promising therapeutic strategy to prevent organ damage and improve survival in sepsis.
  • Further research into C5a-histone interactions may reveal novel therapeutic interventions for sepsis.