Protection Against an Escherichia Coli-Induced Sepsis by Alkaline Phosphatase in Mice

Abstract

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.

Prophylactic Treatment with Alkaline Phosphatase in Cardiac Surgery Induces Endogenous Alkaline Phosphatase Release

“…Reduction of plasma alkaline phosphatase levels after endotoxin administration levels was noted previously by Verweij et al in animal studies (20). Kupffer cells may function to clear the alkaline phosphatase-LPS conjugates from the circulation, thereby reducing the total alkaline phosphatase levels (2,20). This was also demonstrated in our study in the placebo group, who had an initial reduction of plasma alkaline phosphatase.…”

“…Normalized plasma levels were measured after 24 hours postoperatively. Reduction of plasma alkaline phosphatase levels after endotoxin administration levels was noted previously by Verweij et al in animal studies (20). Kupffer cells may function to clear the alkaline phosphatase-LPS conjugates from the circulation, thereby reducing the total alkaline phosphatase levels (2,20).…”

Bovine Intestinal Alkaline Phosphatase Attenuates the Inflammatory Response in Secondary Peritonitis in Mice

“…Therefore, AP effectively detoxifies LPS (16,23,24). In mice, mortality was reduced after lethal injection of gram-negative bacteria and administration of human placental AP (HPLAP) (2) and bovine intestinal AP (BIAP) (30). In rats, endogenous inhibition of intestinal AP led to increased and prolonged endotoxemia after oral LPS challenge compared to control animals (16).…”

“…BIAP was diluted with saline (Fresenius Kabi, 's-Hertogenbosch, The Netherlands) just before i.v. administration in a dose of 0.15 IU/g of body weight, which is approximately 50 to 100 times higher than plasma levels and was previously used by others as well (2,30). BIAP activity was tested by routine laboratory testing.…”

Preoperative Serum Alkaline Phosphatase and Clinical Outcome of Off-Pump Coronary Artery Bypass Surgery

“…13- 15 In a previous study, low postoperative ALP level was associated with worse clinical outcome in infants undergoing cardiothoracic surgery. 16 Therefore, the relationship between ALP and adverse outcome in CABG patients may differ from that in PCI patients.…”