Protection against an Escherichia coli-induced sepsis by alkaline phosphatase in mice.
Alkaline phosphatase (AP) is a phosphate transferase present in bacteria and eukaryotes. In previous studies, we have shown that AP is able to dephosphorylate lipopolysaccharide (LPS) at physiological pH levels. Because LPS is the causative agent of gram-negative sepsis, we hypothesize that AP might be used as a medication during early stages of LPS-induced septic shock. We have demonstrated protective effects of AP when this enzyme was administered simultaneously with LPS. However, a major question of anti-LPS therapies is whether they are also effective after systemic infiltration of whole bacteria and if they also act in later stages of the disease. To test this, we explored the protective effects of AP from human placenta (plAP) in a bacterial challenge model in Balb/c mice. AP was intravenously administered 20 min after a bacterial intraperitoneal inoculation of 2 to 5 x 10 CFU of Escherichia coli suspended in a 100-microL volume of saline. It was shown that AP attenuated the systemic host response upon E. coli. Body temperature was normalized as compared with untreated septic mice. Also, serum nitric oxide levels 24 h after the injection of bacteria were reduced almost to control levels in mice that received AP. Moreover, survival after 24 h was significantly higher in the AP-treated group compared with the nontreated control group.
Verweij
Willem Ronald
WR
Groningen University Institute of Drug Exploration, Department of Pharmacokinetics and Drug Delivery, University of Groningen, The Netherlands. W.R.Verweij@farm.rug.nl
Bentala
Hafida
H
Huizinga-van der Vlag
Ali
A
Miek van Loenen-Weemaes
Anne
A
Kooi
Kor
K
Meijer
Dirk Klaas Fokke
DK
Poelstra
Klaas
K
D000469:Alkaline Phosphatase / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D001831:Body Temperature; D004926:Escherichia coli / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000188:drug therapy*; D006863:Hydrogen-Ion Concentration; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D018805:Sepsis / Q000382:microbiology* / Q000517:prevention & control*; D013234:Stem Cells / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008070:Lipopolysaccharides; D010710:Phosphates; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000469:Alkaline Phosphatase