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Published on: November 5, 2019
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.).
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.
