Intestinal alkaline phosphatase prevents the systemic inflammatory response associated with necrotizing enterocolitis

BackgroundNecrotizing enterocolitis (NEC) is the most common surgical emergency in neonates, with an incidence of 0.5–2.4 cases per 1000 live births and a mortality rate between 10% and 50%. Neonates affected by NEC develop a septic injury that is associated with increased risk of neurological impairment due to intraventricular bleeding and chronic lung disease. Intestinal alkaline phosphatase (IAP) is an endogenous protein that has been shown to inactivate the endotoxin lipopolysaccharide (LPS), and has recently been used successfully as an adjunct to treat sepsis in adult patients. We tested the hypothesis that systemic, exogenous IAP will mitigate the inflammatory response as measured by serum levels of proinflammatory cytokines in a rat model of NEC.MethodsNewborn Sprague-Dawley rats were divided into groups. Control pups were dam fed. NEC was induced by feeding formula containing LPS and exposure to intermittent hypoxia. NEC pups were given intraperitoneal injections of 4 or 40 glycine units (U) of IAP or placebo twice daily. Intestine and serum was collected for cytokine analysis as well as measurement of alkaline phosphatase activity.ResultsSystemic IAP administration significantly increased serum alkaline phosphatase activity in a dose- and time-dependent fashion. The proinflammatory cytokines tumor necrosis factor α, interleukin 6, and interleukin 1β were significantly increased in NEC rats versus controls on days 2 and 3. Importantly, treatment with 40 U systemic IAP decreased these proinflammatory cytokines back to near-control levels.ConclusionsSystemic IAP administration appears effective in mitigating the systemic inflammatory response associated with NEC, and may prove to be a valuable adjunctive treatment for NEC.