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 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.
Matute-Bello
Gustavo
G
Medical Research Service of the Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108-1597, USA. matuteb@u.washington.edu
Liles
W Conrad
WC
Frevert
Charles W
CW
Dhanireddy
Shireesha
S
Ballman
Kimberly
K
Wong
Venus
V
Green
Richard R
RR
Song
Ho Yeong
HY
Witcher
Derrick R
DR
Jakubowski
Joseph A
JA
Martin
Thomas R
TR
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*
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