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

Abstract

Background Necrotizing 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. Methods Newborn 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. Results Systemic 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. Conclusions Systemic IAP administration appears effective in mitigating the systemic inflammatory response associated with NEC, and may prove to be a valuable adjunctive treatment for NEC.

Intestinal alkaline phosphatase to treat necrotizing enterocolitis

“…We suspect once the integrity of this barrier is compromised, there is a very robust local and systemic inflammatory response in which it is difficult for the preterm gut to recover and could contribute to our results. Perhaps combined enteral and intravenous or intraperitoneal supplementation of IAP would be appropriate in this instance, as we have previously shown the ability of intraperitoneal IAP to control systemic inflammation [9]. …”

Intestinal alkaline phosphatase: a summary of its role in clinical disease

“…[51] Subsequent follow-up experiments using the same NEC model have shown enteral IAP decreased both intestinal and systemic inflammatory mediator production as well as improved gut barrier function. [42, 52, 53] While the enteral formulation helped reduce the severity of the intestinal injury, systemic administration did not. However, despite having no effect on intestinal inflammation, systemic IAP was shown to significantly decrease the systemic inflammatory response suggesting that systemic administration of IAP may be useful clinically to treat NEC related sepsis.…”

“…However, despite having no effect on intestinal inflammation, systemic IAP was shown to significantly decrease the systemic inflammatory response suggesting that systemic administration of IAP may be useful clinically to treat NEC related sepsis. [52]…”

“…[52] However, when given by intra-peritoneal injection, IAP decreased the expression of serum cytokines in rat pups with experimental NEC compared to placebo. This suggests that systemic IAP may not prevent NEC but may be useful in combating the systemic sepsis associated with NEC.…”

Intestinal Alkaline Phosphatase Deficiency Leads to Lipopolysaccharide Desensitization and Faster Weight Gain

“…Importantly, ALPs have been shown to remove the lipid A phosphates of the endotoxin lipopolysaccharide (LPS) (7)(8)(9)(10). LPS is a constituent of the outer membrane of Gram-negative bacteria (11) which compose a substantial proportion of the mammalian gut microbiota (12).…”