Calf Intestinal Alkaline Phosphatase, a Novel Therapeutic Drug for Lipopolysaccharide (LPS)-Mediated Diseases, Attenuates LPS Toxicity in Mice and Piglets

Beumer, Chantal; Wulferink, Marty; Raaben, Willem; Fiechter, Daniëlle; Brands, Ruud; Seinen, Willem

doi:10.1124/jpet.103.056606

Cited by 157 publications

(183 citation statements)

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“…The kinetic profile of this plasma alkaline phosphatase level was compatible with the administered alkaline phosphatase with a physical half-life of about 10 minutes (9). Next to the initial increase in alkaline phosphatase level, a significant increase of plasma alkaline phosphatase at 4 to 6 hours postoperatively was observed.…”

Section: Discussionsupporting

confidence: 63%

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

et al. 2012

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Document VersionPublisher's PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication:• A submitted manuscript is the author's version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website.• The final author version and the galley proof are versions of the publication after peer review.• The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publicationCitation for published version (APA): Kats, S., Brands, R., Hamad, M. A., Seinen, W., Scharnhorst, V., Wulkan, R. W., ... Oeveren, van, W. (2014). Prophylactic treatment with alkaline phosphatase in cardiac surgery induces endogenous alkaline phosphatase release. International Journal of Artificial Organs, 35(2), 144-151. DOI: 10.5301/ijao.5000039 General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

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Section: Discussionsupporting

confidence: 63%

“…In previous animal studies, promising therapeutic effects have been shown in reducing the inflammatory response with the use of intravenous alkaline phosphatase (9)(10)(11). In a clinical study in severe sepsis patients, continuous infusion of calf-intestinal alkaline phosphatase significantly improved renal function (12,13).…”

Section: Methodsmentioning

confidence: 97%

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

et al. 2012

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“…AP administration may enhance endogenous dephosphorylating capacity when the need is greatest, such as during acute inflammatory response, to reduce local tissue damage and to retain organ function. Animal models of sepsis have shown exogenous AP to attenuate the inflammatory response and to improve tissue damage and outcomes [16,23] Evaluation of the pharmacokinetics of exogenous AP in humans is complex because the enzyme is also produced endogenously and the activities of endogenous and exogenous enzymes are indistinguishable. We corrected enzyme values for pre-dosing activity, although this does not completely exclude interference from endogenous variations due to circadian and food influences.…”

Section: Discussionmentioning

confidence: 99%

“…Skin-prick tests for sensitization were conducted in studies A and B (volunteers), with the reaction measured as wheal diameter (+ to ++++) Studies A and B were in male healthy volunteers; study C was in sepsis patients of both genders (M males, F females) a Administration of IV LPS (E. coli EC6, 4 ng/kg) for 2 min after 2 min AP infusion start b Administration of IV LPS (E. coli EC6, 4 ng/kg) for 2 min after 2 h AP infusion start tested for AP, for AP buffer solution, and for two controls (one negative: NaCl; one positive: histamine). AP enzyme activity evaluation was by specific kinetic assay described by Beumer [16]. Study medication (active and placebo) was supplied by AM-Pharma BV, The Netherlands, as calf-intestinal alkaline phosphatase in glycerol solution (CAS Registry: EC 3.1.3.1) in 1-mL vials containing AP 5,000 U/mL, complying with the European Union's guidelines on minimization of bovine spongiform encephalopathy (BSE) risk in medicine manufacture [17], approved by the national medicines regulatory authority.…”

Section: Methods Blinding and Subject Selectionmentioning

confidence: 99%

Clinical pharmacology of exogenously administered alkaline phosphatase

Pickkers

Snellen

Rogiers

et al. 2008

Eur J Clin Pharmacol

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Purpose To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). Methods Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg −1 24 h −1 ) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes.Results Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients.

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“…Narisawa et al (19) reported that compared with their wild-type (WT) littermates, mice lacking IAP gained more weight under conditions of a high-fat diet. In addition, several studies have shown that the IAP enzyme is capable of detoxifying LPS, likely through dephosphorylation of the lipid A moiety, the primary source of its endotoxic effects (20). Despite these few reports, the physiological role of IAP within the gut has not been elucidated.…”

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confidence: 99%

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

Goldberg

Austen

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

312

323

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Under conditions of starvation and disease, the gut barrier becomes impaired, and trophic feeding to prevent gut mucosal atrophy has become a standard treatment of critically ill patients. However, the mechanisms responsible for the beneficial effects of enteral nutrition have remained a mystery. Using in vitro and in vivo models, we demonstrate that the brush-border enzyme, intestinal alkaline phosphatase (IAP), has the ability to detoxify lipopolysaccharide and prevent bacterial invasion across the gut mucosal barrier. IAP expression and function are lost with starvation and maintained by enteral feeding. It is likely that the IAP silencing that occurs during starvation is a key component of the gut mucosal barrier dysfunction seen in critically ill patients.A mong the most critical functions of the mammalian gut mucosa is to provide a barrier to luminal microbes and toxins while simultaneously allowing for the necessary digestion and absorption of dietary nutrients. The molecular mechanisms that govern barrier function are incompletely understood, but it is clear that under conditions of starvation and disease, the gut barrier becomes impaired, leading to significant morbidity and mortality (1-8). Trophic enteral feeding to prevent gut mucosal atrophy and resultant barrier dysfunction has become part of the standard treatment of intensive care unit patients (9-14). The mechanism(s) responsible for the beneficial effects of trophic feeding are not understood.Intestinal alkaline phosphatase (IAP), a brush-border protein that hydrolyzes monophosphate esters, is expressed exclusively in villus-associated enterocytes and is considered an excellent marker for crypt-villus differentiation (15-18). Narisawa et al. (19) reported that compared with their wild-type (WT) littermates, mice lacking IAP gained more weight under conditions of a high-fat diet. In addition, several studies have shown that the IAP enzyme is capable of detoxifying LPS, likely through dephosphorylation of the lipid A moiety, the primary source of its endotoxic effects (20). Despite these few reports, the physiological role of IAP within the gut has not been elucidated. Results and DiscussionTo examine the functional role of IAP, we developed in vitro model systems using intestinal cell lines (T84, HT-29, and IEC-6) that express little or no IAP under basal conditions. Stable cell lines were created that overexpress IAP (Fig. 1A), and enzyme assays were used to determine the cellular localization of the ectopically expressed IAP protein. The results in Fig. 1B show that parent cells make little, if any, endogenous IAP. In contrast, large amounts of IAP enzyme are seen in the stably transfected cells. Importantly, the vast majority of the IAP activity is in the membrane fraction as opposed to the cytosol. Fig. 1C shows the results of the control experiment used to validate our separation of membranous and cytosolic fractions, confirming that the majority of the MAPK enzyme activity exists within the cytosol rather than the membrane. This membrane ...

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Calf Intestinal Alkaline Phosphatase, a Novel Therapeutic Drug for Lipopolysaccharide (LPS)-Mediated Diseases, Attenuates LPS Toxicity in Mice and Piglets

Cited by 157 publications

References 34 publications

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

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

Clinical pharmacology of exogenously administered alkaline phosphatase

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

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