Abstract
Alkaline phosphatase (AP) is an enzyme that exhibits anti-inflammatory effects by dephosphorylating inflammation triggering moieties (ITMs) like bacterial lipopolysaccharides and extracellular nucleotides. AP administration aims to prevent and treat peri- and post-surgical ischemia reperfusion injury in cardiothoracic surgery patients. Recent studies reported that intravenous bolus administration and continuous infusion of AP in patients undergoing coronary artery bypass grafting with cardiac valve surgery induce an increased release of liver-type “tissue non-specific alkaline phosphatase” (TNAP) into the bloodstream. The release of liver-type TNAP into circulation could be the body's way of strengthening its defense against a massive ischemic insult. However, the underlying mechanism behind the induction of TNAP is still unclear. To obtain a deeper insight into the role of AP during surgery, we developed a mathematical model of systemic inflammation that clarifies the relation between supplemented AP and TNAP and describes a plausible induction mechanism of TNAP in patients undergoing cardiothoracic surgery. The model was validated against clinical data from patients treated with bovine Intestinal AP (bIAP treatment) or without AP (placebo treatment), in addition to standard care procedures. We performed additional in-silico experiments adding a secondary source of ITMs after surgery, as observed in some patients with complications, and predicted the response to different AP treatment regimens. Our results show a strong protective effect of supplemented AP for patients with complications. The model provides evidence of the existence of an induction mechanism of liver-type tissue non-specific alkaline phosphatase, triggered by the supplementation of AP in patients undergoing cardiac surgery. To the best of our knowledge this is the first time that a quantitative and validated numerical model of systemic inflammation under clinical treatment conditions is presented.
Highlights
Humans have four distinct Alkaline phosphatase (AP) isozymes: tissue-nonspecific AP, which is the most predominant circulating form of isozyme, intestinal, placental-type, and germ cell AP
We develop a new model of systemic inflammation based on existing models of the innate immune response to acute inflammation [25,26,27,28,29,30,31,32], with the purpose of describing, and gaining further insight on the dynamics of the innate immune system response through in-silico experiments [33]
In the second sub-section we show the dynamics of all cellular and molecular entities in the model and highlight the action of bovine intestinal AP (bIAP) on the dynamics of systemic inflammation
Summary
Alkaline Phosphatase (AP) is an enzyme originally known for its pivotal role in skeletal mineralization [1] and for its capability to reduce inflammation. A study in 2012 by Kats et al [24] demonstrated that intravenous bolus administration and continuous infusion of bovine intestinal Alkaline Phosphatase [bIAP, bRESCAP, and APPIRED studies by Alloksys Life Sciences [7, 9]], in patients undergoing CABG (with or without valve surgery) results in the release of endogenous tissue non-specific AP (TNAP), most likely liver-type AP. This release exhibits a unique feat that was not before observed in septic shock patients [19]. We construct the HIIS model from Reynolds et al [28], Su et al [31], and Pigozzo et al [32] by introducing the following key differences: compartmentalization of the organism into liver, blood and tissue; introduction of the dual pathway to neutrophils death, necrosis being pro-inflammatory and apoptosis being anti-inflammatory; introduction of the antiinflammatory action of AP and of the mechanism of AP induction; the dilution of cellular components in tissue typical of systemic inflammatory responses as opposed to the increased concentration of cellular components in a localized region typical of acute inflammatory responses
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