Enhanced survival from cecal ligation and puncture with pentoxifylline is associated with altered neutrophil trafficking and reduced interleukin-1 beta expression but not inhibition of tumor necrosis factor synthesis.
BACKGROUND
Our preliminary results showed that pentoxifylline improves survival after cecal ligation and puncture (CLP), even though in this model inhibition of tumor necrosis factor (TNF) activity decreases survival. In this study we tested the hypothesis that pentoxifylline improves survival after CLP, not by inhibiting TNF synthesis but by exerting its effect on leukocyte adhesiveness, neutrophil sequestration, recruitment of cells into the focus of sepsis, and interleukin-1 (IL-1) expression.


METHODS
Pentoxifylline, 10 or 100 mg/kg/day, was administered to mice after CLP by infusion for 3 days. The following was measured at 24 hours for the group with improved survival: (1) serum TNF by enzyme-linked immunosorbent assay, (2) TNF and IL-1 beta mRNAs in lung and peritoneal macrophages by the differential polymerase chain reaction, (3) lung myeloperoxidase by a colorimetric assay, (4) leukocyte CD11b/CD18 by flow cytometry, and (5) peritoneal exudate cells by manual counting.


RESULTS
Only the low-dose pentoxifylline increased survival. Pentoxifylline reduced IL-1 beta mRNA expression in lung and peritoneal macrophages but not TNF mRNA or immunoreactive TNF in the serum. The myeloperoxidase content of lung was reduced by pentoxifylline, but leukocyte CD11b/CD18 expression did not change. Pentoxifylline increased the number of cells in the peritoneum after CLP.


CONCLUSIONS
Pentoxifylline improves survival after CLP without inhibiting TNF synthesis or expression of CD11b/CD18 on leukocytes. Pentoxifylline treatment reduced lung neutrophil sequestration and IL-1 beta mRNA levels and increased cell recruitment in the peritoneum.
Hadjiminas
D J
DJ
Department of Surgery, University of Louisville, KY 40292.
McMasters
K M
KM
Robertson
S E
SE
Cheadle
W G
WG
D000818:Animals; D016470:Bacteremia / Q000378:metabolism / Q000401:mortality*; D002432:Cecum / Q000601:surgery; D002465:Cell Movement; D004195:Disease Models, Animal; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008026:Ligation; D016177:Macrophage-1 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000502:physiology*; D010431:Pentoxifylline / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D007375:Interleukin-1; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D010431:Pentoxifylline