Critical Care Medicine  |   April 2020
Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis
Author Notes
  • From the Division of Pulmonary Inflammation (H.M.-R., S.-M.W., B.G., J.L., K.H., K.R., E.L., M.W.) and 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.); and German Center for Lung Research, Giessen, Germany (associate members N.S., M.W.). Current Position: Takeda GmbH, Oranienburg, Germany (C.M.); and APTARION biotech AG, Berlin, Germany (K.H., S.K., A.V.).
  • This article is featured in “This Month in Anesthesiology,” page 1A.
    This article is featured in “This Month in Anesthesiology,” page 1A.×
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    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • This article has a video abstract.
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  • Part of the work presented in this article has been presented at the American Thoracic Society 2014 International Conference in San Diego, California, May 16 to 21, 2014; the European Respiratory Society International Congress in Munich, Germany, September 6 to 10, 2014; and the 37th Annual Conference of the Shock Society, Charlotte, North Carolina, June 7 to 10, 2014.
    Part of the work presented in this article has been presented at the American Thoracic Society 2014 International Conference in San Diego, California, May 16 to 21, 2014; the European Respiratory Society International Congress in Munich, Germany, September 6 to 10, 2014; and the 37th Annual Conference of the Shock Society, Charlotte, North Carolina, June 7 to 10, 2014.×
  • Submitted for publication December 11, 2018. Accepted for publication December 20, 2019. Published online first on February 20, 2020.
    Submitted for publication December 11, 2018. Accepted for publication December 20, 2019. Published online first on February 20, 2020.×
  • Address correspondence to Dr. Witzenrath: Division of Pulmonary Inflammation, and Department of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. martin.witzenrath@charite.de. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Critical Care Medicine / Basic Science / Critical Care / Infectious Disease / Respiratory System
Critical Care Medicine   |   April 2020
Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis
Anesthesiology 4 2020, Vol.132, 795-807. doi:https://doi.org/10.1097/ALN.0000000000003149
Anesthesiology 4 2020, Vol.132, 795-807. doi:https://doi.org/10.1097/ALN.0000000000003149
Abstract

Background: Community-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions. The authors hypothesized that C5a concentrations are increased in pneumonia and C5a neutralization promotes barrier stabilization in the lung and is protective in pneumococcal pulmonary sepsis.

Methods: The authors investigated regulation of C5a in pneumonia in a prospective patient cohort and in experimental pneumonia. Two complementary models of murine pneumococcal pneumonia were applied. Female mice were treated with NOX-D19, a C5a-neutralizing l-RNA-aptamer. Lung, liver, and kidney injury and the inflammatory response were assessed by measuring pulmonary permeability (primary outcome), pulmonary and blood leukocytes, cytokine concentrations in lung and blood, and bacterial load in lung, spleen, and blood, and performing histologic analyses of tissue damage, apoptosis, and fibrin deposition (n = 5 to 13).

Results: In hospitalized patients with pneumonia (n = 395), higher serum C5a concentrations were observed compared to healthy subjects (n = 24; 6.3 nmol/l [3.9 to 10.0] vs. 4.5 nmol/l [3.8 to 6.6], median [25 to 75% interquartile range]; difference: 1.4 [95% CI, 0.1 to 2.9]; P = 0.029). Neutralization of C5a in mice resulted in lower pulmonary permeability in pneumococcal pneumonia (1.38 ± 0.89 vs. 3.29 ± 2.34, mean ± SD; difference: 1.90 [95% CI, 0.15 to 3.66]; P = 0.035; n = 10 or 11) or combined severe pneumonia and mechanical ventilation (2.56 ± 1.17 vs. 7.31 ± 5.22; difference: 4.76 [95% CI, 1.22 to 8.30]; P = 0.011; n = 9 or 10). Further, C5a neutralization led to lower blood granulocyte colony-stimulating factor concentrations and protected against sepsis-associated liver injury.

Conclusions: Systemic C5a is elevated in pneumonia patients. Neutralizing C5a protected against lung and liver injury in pneumococcal pneumonia in mice. Early neutralization of C5a might be a promising adjunctive treatment strategy to improve outcome in community-acquired pneumonia.

Editor’s Perspective:

What We Already Know about This Topic:

  • Pneumonia, sepsis, and immune dysregulation cause morbidity and mortality

  • C5a is a component of the complement system and a proinflammatory mediator that modulates the innate immune response in critical illness

  • Disruption of the C5a receptor axis with antibodies or antagonists was previously protective in various animal sepsis models

What This Article Tells Us That Is New:

  • In hospitalized patients with community-acquired pneumonia, serum C5a concentrations were 1.4-fold higher compared to healthy subjects

  • In two mouse models of pneumonia and sepsis, NOX-D19, a C5a-neutralizing l-RNA-aptamer, caused lower pulmonary hyperpermeability and sepsis-related acute liver injury