title: Blockade of the Fas/FasL system improves pneumococcal clearance from the lungs without preventing dissemination of bacteria to the spleen.
abstract: 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 105 or 1.9 x 107 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, 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, 19.3%+/-9.5% and 20.2%+/-7.8%, respectively, vs. 55.0%+/-12.2% in untreated C57Bl/6 mice; P<.05). These changes were associated 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.
  
  
  CONCLUSIONS
  Blockade of the Fas/FasL system by DcR3-a in the lungs improves clearance of bacteria in mice with pneumococcal pneumonia.
authors.affiliation: Medical Research Service of the Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108-1597, USA. matuteb@u.washington.edu
authors.forename: Gustavo
authors.initials: G
authors.lastname: Matute-Bello
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Charles W
authors.initials: CW
authors.lastname: Frevert
authors.forename: Shireesha
authors.initials: S
authors.lastname: Dhanireddy
authors.forename: Kimberly
authors.initials: K
authors.lastname: Ballman
authors.forename: Venus
authors.initials: V
authors.lastname: Wong
authors.forename: Richard R
authors.initials: RR
authors.lastname: Green
authors.forename: Ho Yeong
authors.initials: HY
authors.lastname: Song
authors.forename: Derrick R
authors.initials: DR
authors.lastname: Witcher
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054426:Chemokine CXCL2; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D008168:Lung / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015846:Monokines / Q000032:analysis; D009154:Mutation; D010587:Phagocytosis; D011018:Pneumonia, Pneumococcal / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000008:administration & dosage / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D013154:Spleen / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000276:immunology* / Q000302:isolation & purification; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
chemical_list: D054426:Chemokine CXCL2; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D015846:Monokines; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor