Pneumologie 2014; 68 - A35
DOI: 10.1055/s-0033-1363128

Neutralizing the complement component C5a protects against lung injury and extrapulmonary organ injury in pneumococcal pneumonia induced sepsis

HC Müller-Redetzky 1, U Henke-Kellermann 1, T Tschernig 2, S Wienhold 1, M Polikarpova 1, K Hellwig 1, A Vater 4, C Maasch 4, S Klussman 4, MD Menger 3, N Suttorp 1, M Witzenrath 1
  • 1Charité – Universitätsmedizin Berlin, Dept. of Infectious Diseases and Pulmonary Medicine, Berlin
  • 2Institute of Anatomy and Cell Biology, Saarland University, Faculty of Medicine, Homburg
  • 3Institute for Clinical and Experimental Surgery, Saarland University, Faculty of Medicine, Homburg
  • 4NOXXON Pharma, Berlin

Rationale: Severe community acquired pneumonia (sCAP) and resultant sepsis cause high lethality despite adequate antibiotic treatment. S. pneumoniae is the most prevalent causative pathogen of sCAP. Uncontrolled inflammatory host responses likely contribute to unfavourable outcome by aggravating lung and extrapulmonary organ injury. The complement system is involved in the immune response against infection but also contributes to hyperinflammation and vascular barrier failure mainly mediated by the complement fragment C5a, an anaphylatoxin. We thus aimed to investigate the regulation of C5a in pneumonia and hypothesized that in pneumococcal pneumonia neutralizing C5a by NOX-D19, a PEGylated 44 nucleotide L-RNA aptamer (Spiegelmer), would ameliorate pulmonary vascular barrier failure, modulate the inflammatory host response and protect against extrapulmonary organ failure in sepsis.

Methods: Mice were infected with S. pneumoniae. NOX-D19 was applied i.p. 24 and 48 h post infection. Measurements of pulmonary permeability, pulmonary and blood leukocytes, and levels of IL-1β, GSF, KC and IL-6, bacterial load in lung, spleen and blood, markers of liver and kidney function (AST, BUN) and histological analyses of fibrin deposition in the liver were performed.

Results: C5a levels increased during pneumonia in lung and blood reaching a maximum 24 h post infection. Pulmonary leukocyte counts and cytokine levels were increased, and moderate pulmonary vascular permeability and bacteraemia had developed 24 h post infection, reflecting severe pneumonia. Lung failure and septic extra pulmonary organ injury developed within 48 h post infection, displayed by a further increase of pulmonary permeability and blood cytokine levels, as well as increased AST and BUN. Hepatic fibrin deposition reflected microcirculatory failure. NOX-D19 attenuated pulmonary permeability, reduced blood cytokine levels, protected against liver injury as judged by reduced AST levels, and abrogated hepatic fibrin deposition 48 h post infection.

Conclusion: Neutralizing C5a by NOX-D19 protected against lung and extrapulmonary organ failure in pneumococcal pneumonia-induced sepsis. C5a neutralization thus may offer an adjuvant treatment strategy in pneumococcal sepsis.