Pneumonia and resultant sepsis cause high lethality despite antibiotic treatment. Uncontrolled inflammatory host responses likely contribute to unfavourable outcome by driving lung and extrapulmonary organ injury. The complement system contributes to hyperinflammation and vascular barrier failure mainly mediated by the complement fragment C5a. We investigated regulation of C5a in pneumonia and hypothesized that in pneumonia neutralizing C5a by NOX-D19 (Spiegelmer), would protect against pulmonary and extrapulmonary organ failure. Mice infected with S. pneumonia were treated with NOX-D19. Pulmonary permeability, pulmonary and blood leukocytes, IL-1b, GSF, KC and IL-6, bacterial load in lung, spleen and blood liver and kidney function and histological analyses of fibrin deposition and apoptosis in the liver were analysed. C5a increased in pneumonia. Lung leukocytes and cytokine increased, and moderate pulmonary permeability and bacteraemia had developed 24 h post infection. Lung failure and septic extra pulmonary organ injury developed within 48 h, 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 was accompanied by apoptosis of hepatocytes. NOX-D19attenuated pulmonary permeability, reduced blood cytokine levels, protected against liver injury as judged by reduced AST levels, and abrogated hepatic fibrin deposition as well as apoptosis of hepatocytes 48 h post infection. Conclusion : Neutralizing C5a by NOX-D19 protected against lung and extrapulmonary organ failure in pneumonia-induced sepsis.
Holger et al. (Mon,) studied this question.