Publikationsdatenbank

Neutralizing complement C5a protects mice with pneumococcal pulmonary sepsis (2020)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Müller-Redetzky, Holger

Kellermann, Ute

Wienhold, Sandra-Maria

Gutbier, Birgitt

Lienau, Jasmin

Hellwig, Katharina

Reppe, Katrin

Letsiou, Eleftheria

Tschernig, Thomas

Scholz, Markus

Ahnert, Peter

Maasch, Christian

Hoehlig, Kai

Klussmann, Sven

Vater, Axel

Firsching, Theresa C. (WE 12)

Hoppe, Judith (WE 12)

Suttorp, Norbert

Witzenrath, Martin

Quelle

Anesthesiology : the journal of the American Society of Anesthesiologists

Bandzählung: 132

Heftzählung: 4

Seiten: 795 – 807

ISSN: 1528-1175

Sprache

Englisch

Verweise

URL (Volltext): https://anesthesiology.pubs.asahq.org/article.aspx?articleid=2761899

DOI: 10.1097/ALN.0000000000003149

Pubmed: 32101978

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.