Blockade of the Fas/FasL system improves pneumococcal clearance from the lungs without preventing dissemination of bacteria to the spleen

Background. The Fas/FasL system is both proapoptotic and proinflammatory. FasL is inhibited by decoy receptor-3 (DcR3), a naturally occurring decoy receptor. We determined the effects of systemic blockade of the Fas/FasL system by a DcR3 analog (DcR3-a) in mice with pneumococcal pneumonia. Methods. Streptococcus pneumoniae (7.2 x 10(5) or 1.9 x 10(7) cfu/mL) was instilled intratracheally into untreated C57Bl/6 mice, C57Bl/6 mice treated with DcR3-a, or Fas-deficient lpr mice, and the mice were studied 48 h later. Results. After instillation of the lower bacterial dose, disruption of the Fas/FasL system by either DcR3-a or the lpr mutation resulted in improved clearance of bacteria in the lungs (mean +/- SE, and 4.6 +/- 2.1 x 10(6) and 3.5 +/- 1.6 x 10(6) cfu/lung, respectively, vs. 21.9 +/- 9.3 x 10(6) cfu/lung in untreated C57Bl/6 mice; P < .05) and decreased percentage of polymorphonuclear neutrophils in bronchoalveolar lavage fluid (mean +/- SE, and 19.3% +/- 9.5%, respectively, vs. in untreated C57Bl/ 6 mice;). These changes were associated 20.2% +/- 7.8% 55.0% +/- 12.2% P < .05 with decreased lung concentrations of the proinflammatory cytokines tumor necrosis factor-alpha and macrophage inflammatory protein-2 and with a decrease in apoptotic cells in the alveolar walls. Conclusion. Blockade of the Fas/FasL system by DcR3-alpha in the lungs improves clearance of bacteria in mice with pneumococcal pneumonia.