A novel role of alkaline phosphatase in protection from immunological liver injury in mice

Xu, Qiang; Lu, Ziwei; Zhang, Xianming

doi:10.1034/j.1600-0676.2002.220102.x

Cited by 25 publications

(21 citation statements)

References 13 publications

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“…After exposure to LPS both in vitro and in vivo, hepatocellular damage was increased when AP synthesis was inhibited. It was suggested that high levels of AP exert a protective effect against liver damage by neutralizing endotoxin (33). In the present study, this protective effect was observed in the prophylaxis group but not in the early treatment group.…”

Section: Discussionsupporting

confidence: 68%

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

et al. 2005

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Lipopolysaccharide (LPS) contributes importantly to morbidity and mortality in sepsis. Bovine intestinal alkaline phosphatase (BIAP) was demonstrated to detoxify LPS through dephosphorylation. LPS injection combined with BIAP reduced inflammation and improved survival in various experimental settings. In this study, single-dose intravenous administration of BIAP (0.15 IU/g) was applied in a murine cecal ligation and puncture (CLP) model of polymicrobial sepsis. Saline was given as control (S group). Treatment with BIAP prior to CLP (prophylaxis; BIAP-P group) or shortly after (early treatment; BIAP-ET group) reduced cytokine concentrations in plasma and peritoneal lavage fluid (PLF). Tumor necrosis factor-alpha peak levels decreased from 170 pg/ml (S) to 57.5 (BIAP-P) and 82.5 (BIAP-ET) in plasma and in PLF from 57.5 pg/ml (S) to 35.3 (BIAP-P) and 16.8 (BIAP-ET) (all, P < 0.05). Peak interleukin-6 levels in plasma decreased from 19.3 ng/ml (S) to 3.4 (BIAP-P) and 11.5 (BIAP-ET) and in PLF from 32.6 ng/ml (S) to 13.4 (BIAP-P) and 10.9 (BIAP-ET) (all, P < 0.05). Macrophage chemoattractant protein 1 peak levels in plasma decreased from 2.0 ng/ml (S) to 1.0 (BIAP-P) and 0.7 (BIAP-ET) and in PLF from 6.4 (S) to 2.3 (BIAP-P) and 1.3 ng/ml (BIAP-ET) (all, P < 0.05). BIAP-treated groups showed decreased transaminase activity in plasma and decreased myeloperoxidase activity in the lung, indicating reduced associated hepatocellular and pulmonary damage. Survival was not significantly altered by BIAP in this single-dose regimen. In polymicrobial secondary peritonitis, both prophylactic and early BIAP treatment attenuates the inflammatory response both locally and systemically and reduces associated liver and lung damage.Secondary peritonitis can ultimately lead to sepsis with shock and/or organ failure and is associated with high morbidity and mortality (30 to 40%) (5). Both secondary peritonitis and sepsis are characterized by an excessive inflammatory response (7, 28). Activation of cytokines and other inflammatory mediators in these conditions are induced by endotoxins, such as lipopolysaccharide (LPS), which is an important contributor to morbidity and mortality (28). LPS is a component of the outer leaflet of gram-negative bacteria. It is a complex and negatively charged molecule composed of a polysaccharide chain (O-specific chain) and a toxic lipid moiety (lipid A). The two phosphate groups of lipid A are essential for its immunostimulatory characteristics (2, 7). Intravenous (i.v.) injection of LPS leads to a generalized inflammatory response (29). The dephosphorylation product of lipid A, monophosphoryl lipid A, is a nontoxic derivative that does not evoke major inflammatory response (2) and is known to induce tolerance (1, 34). Therefore, LPS (and, in particular, lipid A) is a potential therapeutic target in sepsis (7, 11). Many sepsis therapies have aimed to block the effect of LPS by using antisera (6, 35) and anti-LPS antibodies (20) or by binding LPS with LPS-binding protein (8) or high-density lipoprotein (1...

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Section: Discussionsupporting

confidence: 68%

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

et al. 2005

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“…Enhanced TNAP levels have been observed in leukocytes from patients with Gram-negative sepsis (Chikkappa 1992). Administration of lipopolysaccharide (LPS)-a constitutent of the outer membrane of Gram-negative bacteria-induced systemic up-regulation of TNAP (Xu et al 2002).…”

Section: Introductionmentioning

confidence: 99%

High Level Expression of Tissue-Nonspecific Alkaline Phosphatase in the Milk of Transgenic Rabbits

et al. 2006

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Alkaline phosphatase is a promising therapeutic agent in the Gram-negative bacterial lipopolysaccharide (LPS) mediated acute and chronic diseases. Contrary to other alkaline phosphatase isozymes, purified tissue-nonspecific alkaline phosphatase (TNAP) is not available in large quantities from tissue sources, which would enable to analyse its efficacy in animal sepsis models. Two transgenic rabbit lines were created by pronuclear microinjection with the whey acidic protein promoter-humanTNAP minigene (WAP-hTNAP). Lactating females of both lines produced biologically active human TNAP. As indicated by fractionation of milk samples the recombinant alkaline phosphatase was associated with the membrane of milk fat globules. Alkaline phosphatase enzymatic activity was two orders of magnitude higher compared to normal human serum levels. The demonstration that this TNAP is physiologically active would provide the clue to use transgenic animals as bioreactor for bulk production of the human tissue-nonspecific alkaline phosphatase in milk. This may be a valuable and possibly viable option with important implication in attenuating LPS mediated inflammatory responses.

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“…Although inhibition of endogenous alkaline phosphatase synthesis has been shown to increase hepatic injury after LPS challenge 39 , endogenous alkaline phosphatase probably played only a minor role in the present study. Plasma alkaline phosphatase activity did not increase significantly after I/R throughout the reperfusion phase.…”

Section: Hepatic and Pulmonary Histopathologymentioning

confidence: 92%

Alkaline phosphatase reduces hepatic and pulmonary injury in liver ischaemia–reperfusion combined with partial resection

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et al. 2006

British Journal of Surgery

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A novel role of alkaline phosphatase in protection from immunological liver injury in mice

Cited by 25 publications

References 13 publications

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

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

High Level Expression of Tissue-Nonspecific Alkaline Phosphatase in the Milk of Transgenic Rabbits

Alkaline phosphatase reduces hepatic and pulmonary injury in liver ischaemia–reperfusion combined with partial resection

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