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Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis.

Holger Müller-Redetzky1, Ute Kellermann, Sandra-Maria Wienhold

  • 1From the Division of Pulmonary Inflammation (H.M.-R., S.-M.W., B.G., J.L., K.H., K.R., E.L., M.W.) the Department of Infectious Diseases and Respiratory Medicine (H.M.-R., U.K., N.S., M.W.), Charité - University Medicine Berlin (Charité - Universitätsmedizin Berlin), corporate member of Free University of Berlin (Freie Universität Berlin), Humboldt University of Berlin (Humboldt-Universität zu Berlin), and Berlin Institute of Health, Berlin, Germany Institute of Anatomy and Cell Biology, Saarland University, Homburg/Saar, Germany (T.T.) Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany (M.S., P.A.) NOXXON Pharma AG, Berlin, Germany (C.M., K.H., S.K., A.V.) Institute of Veterinary Pathology, Free University of Berlin (Freie Universität Berlin), Berlin, Germany (T.C.F., J.H.) German Center for Lung Research, Giessen, Germany (associate members N.S., M.W.).

Anesthesiology
|February 27, 2020
PubMed
Summary
This summary is machine-generated.

Elevated C5a levels in pneumonia patients were observed. Neutralizing C5a protected against lung and liver injury in mouse models, suggesting it as a potential adjunctive therapy for community-acquired pneumonia.

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Area of Science:

  • Immunology
  • Pulmonology
  • Critical Care Medicine

Background:

  • Community-acquired pneumonia and sepsis lead to high mortality, often due to uncontrolled inflammatory responses causing organ failure.
  • The complement fragment C5a is a potent pro-inflammatory mediator implicated in tissue damage across various inflammatory conditions.
  • This study investigated the role of C5a in pneumonia and its potential as a therapeutic target.

Purpose of the Study:

  • To determine if C5a concentrations are elevated in patients with pneumonia.
  • To evaluate the therapeutic potential of C5a neutralization in experimental pneumococcal pneumonia and sepsis.
  • To assess the impact of C5a neutralization on lung barrier function and organ injury.

Main Methods:

  • Serum C5a levels were measured in hospitalized pneumonia patients (n=395) and healthy controls (n=24).
  • Experimental pneumococcal pneumonia was induced in mice, with some treated with a C5a-neutralizing aptamer (NOX-D19).
  • Outcomes assessed included pulmonary permeability, leukocyte counts, cytokine levels, bacterial load, and histological analysis of tissue damage.

Main Results:

  • Patients with pneumonia exhibited significantly higher serum C5a concentrations compared to healthy subjects.
  • C5a neutralization in mice reduced pulmonary permeability in pneumococcal pneumonia models, including those with mechanical ventilation.
  • Treatment with the C5a-neutralizing aptamer also decreased pro-inflammatory cytokines and protected against sepsis-associated liver injury.

Conclusions:

  • Systemic C5a is elevated in pneumonia patients, correlating with disease severity.
  • Neutralizing C5a demonstrated protective effects against lung and liver injury in preclinical models of pneumococcal pneumonia.
  • Targeting C5a early in the disease course may represent a promising adjunctive treatment strategy for community-acquired pneumonia.