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

It has been demonstrated that human placental alkaline phosphatase (HPLAP) attenuates the lipopolysaccharide (LPS)-mediated inflammatory response, likely through dephosphorylation of the lipid A moiety of LPS. In this study, it is demonstrated that also alkaline phosphatase derived from calf intestine (CIAP) is able to detoxify LPS. In mice administered CIAP, 80% of the animals survived a lethal Escherichia coli infection. In piglets, previous to LPS detoxification, the pharmacokinetic behavior of CIAP was studied. CIAP clearance was shown to be dose-independent and showed a biphasic pattern with an initial t1/2 of 3 to 5 min and a second phase t1/2 of 2 to 3 h. Although CIAP is cleared much faster than HPLAP, it attenuates LPS-mediated effects on hematology and tumor necrosis factor-α responses at doses up to 10 μg/kg in piglets. LPS-induced hematological changes were antagonized, and the tumor necrosis factor-α response was reduced up to 98%. Daily i.v. bolus administration of 4000 units CIAP, the highest dose used in the LPS intervention studies, in piglets for 28 days was tolerated without any sign of toxicity. Therefore, CIAP potentially encompasses a novel therapeutic agent in the treatment of LPS-mediated diseases. Based on the data mentioned above, human clinical trials have been initiated.

[1]  E. Rietschel,et al.  Pathology of Septic Shock , 2011, Current Topics in Microbiology and Immunology.

[2]  D. Meijer,et al.  A kinetic study of hepatic uptake of canine intestinal alkaline phosphatase in the rat. , 2008, Liver.

[3]  D. Meijer,et al.  Removal of Phosphate from Lipid A as a Strategy to Detoxify Lipopolysaccharide , 2002, Shock.

[4]  T. Matsunaga,et al.  Alkaline phosphatases reduce toxicity of lipopolysaccharides in vivo and in vitro through dephosphorylation. , 2002, Clinical biochemistry.

[5]  K. Triantafilou,et al.  Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. , 2002, Trends in immunology.

[6]  Ruslan Medzhitov,et al.  Control of adaptive immune responses by Toll-like receptors. , 2002, Current opinion in immunology.

[7]  M. Andonova,et al.  Changes in some factors of the innate immunity and serum zinc and iron concentrations in pigs following intravenous administration of Escherichia coli lipopolysaccharide. , 2001, The Onderstepoort journal of veterinary research.

[8]  T. Shimosegawa,et al.  Ulcerative Colitis is Associated with a Promoter Polymorphism of Lipopolysaccharide Receptor Gene, CD14 , 2001, Scandinavian journal of gastroenterology.

[9]  J Ean,et al.  Efficacy and safety of recombinant human activated protein C for severe sepsis. , 2001, The New England journal of medicine.

[10]  J. Verhoef,et al.  Analysis of lipopolysaccharide (LPS)-binding characteristics of serum components using gel filtration of FITC-labeled LPS. , 2000, Journal of immunological methods.

[11]  L. Howe.  Novel agents in the therapy of endotoxic shock , 2000, Expert opinion on investigational drugs.

[12]  R. Munford,et al.  Lipopolysaccharide-Binding Protein and Phospholipid Transfer Protein Release Lipopolysaccharides from Gram-Negative Bacterial Membranes , 2000, Infection and Immunity.

[13]  G. Dickneite,et al.  Influence of antithrombin III on coagulation and inflammation in porcine septic shock. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[14]  S. Lowry,et al.  The Human Response to Endotoxin , 1998 .

[15]  R. Schumann.  Recognition of Bacterial Endotoxin and Modulation of the Inflammatory Response: The LBP/CD14 Pathway During the Acute Phase , 1998 .

[16]  D. Meijer,et al.  Dephosphorylation of endotoxin by alkaline phosphatase in vivo. , 1997, The American journal of pathology.

[17]  D. Baker,et al.  Time course of increased plasma cytokines, cortisol, and urea nitrogen in pigs following intraperitoneal injection of lipopolysaccharide. , 1997, Journal of animal science.

[18]  D. Meijer,et al.  A physiologic function for alkaline phosphatase: endotoxin detoxification. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[19]  M. Tykocinski,et al.  Cell‐surface engineering with GPI‐anchored proteins , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  L. V. D. van der Ploeg,et al.  Thermal and behavioral effects of lipopolysaccharide and influenza in interleukin-1 beta-deficient mice. , 1995, The American journal of physiology.

[21]  G. Makhlouf,et al.  Functional characterization of phosphoinositide-specific phospholipase C-beta 1 and -beta 3 in intestinal smooth muscle. , 1995, The American journal of physiology.

[22]  G. Watanabe,et al.  Lipopolysaccharide-induced apoptosis in swine lymphocytes in vivo , 1995, Infection and immunity.

[23]  W. Hoffmann,et al.  Glucocorticoid hepatopathy: effect on receptor-mediated endocytosis of asialoglycoproteins. , 1991, Biochemical medicine and metabolic biology.

[24]  W. Fishman.  Alkaline phosphatase isozymes: recent progress. , 1990, Clinical biochemistry.

[25]  E. Draper,et al.  APACHE II: A severity of disease classification system , 1985, Critical care medicine.

[26]  J. Wiggins,et al.  Influence of fine structure of lipid A on Limulus amebocyte lysate clotting and toxic activities , 1984, Infection and immunity.

[27]  N. Qureshi,et al.  Separation and characterization of toxic and nontoxic forms of lipid A. , 1984, Reviews of infectious diseases.

[28]  D. B. Zilversmit,et al.  Role of phosphatidylinositol in attachment of alkaline phosphatase to membranes. , 1980, Biochemistry.

[29]  W. Hoffmann,et al.  Serum half-life of intravenously injected intestinal and hepatic alkaline phosphatase isoenzymes in the cat. , 1977, American journal of veterinary research.

[30]  Hoffmann We,et al.  Disappearance rates of intravenously injected canine alkaline phosphatase isoenzymes. , 1977 .

[31]  G. Ashwell,et al.  The binding of desialylated glycoproteins by plasma membranes of rat liver. , 1971, The Journal of biological chemistry.

[32]  S. Opal,et al.  The Sepsis Text , 2002, Springer US.

[33]  J. Robotham,et al.  The acute-phase response. , 1995, New horizons.

[34]  S. Treon,et al.  CD14 mediated endogenous TNF-alpha release in HL60 AML cells: a potential model for CD14 mediated endogenous cytokine release in the treatment of AML. , 1994, Leukemia research.

[35]  J. Trowsdale,et al.  Alkaline phosphatases. , 1990, Biochemical Society transactions.

[36]  W. Hoffmann,et al.  Disappearance rates of intravenously injected canine alkaline phosphatase isoenzymes. , 1977, American journal of veterinary research.

[37]  A. Morell,et al.  A membrane receptor protein for asialoglycoproteins. , 1974, Methods in enzymology.

[38]  A. Morell,et al.  [87] A membrane receptor protein for asialoglycoproteins , 1974 .