Fundamental Toxicological Sciences

Paper Details

Fundamental Toxicological Sciences
Vol. 8 No. 3 July 27, 2021 p.89-96
Original Article
Inorganic polyphosphate modulates leukocyte accumulation and vascular endothelial cell permeability and ameliorates cecal ligation and puncture-induced lethality
  • Satoshi Numazawa (Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy / Pharmacology Research Center, Showa University /
Yoshitaka Yamazaki 1) 2) , Mikako Terashima-Hasegawa 3) , Atsufumi Manabe 3) , Toshikazu Shiba 3) 4) , Yumi Kawazoe 1) 4) , Takashi Ashino 1) 2) , Masahiro Hosonuma 5) , Satoshi Numazawa 1) 2)
1) Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy , 2) Pharmacology Research Center, Showa University , 3) Division of Aesthetic Dentistry and Clinical Cariology, Department of Conservative Dentistry, Showa University School of Dentistry , 4) Regenetiss Inc. , 5) Department of Clinical Immuno-oncology, Clinical Research Institute of Clinical Pharmacology and Therapeutics, Showa University
Keywords: Sepsis, Inorganic polyphosphates, Cecal ligation and puncture, Vascular permeability

Inorganic polyphosphates with an average degree of polymerization of 150 (polyP150) have been shown to improve mortality in a lipopolysaccharide model of sepsis in mice. We aimed to investigate the effects of polyP150 in a mouse model of cecal ligation and puncture (CLP) peritonitis, which accurately reflects clinical sepsis, and elucidate its mechanism of action and suitability as a candidate for sepsis treatment. The present study demonstrated that treatment with polyP150 significantly improved survival rate in mouse model of CLP peritonitis. polyP150 inhibited a CLP-mediated increase in pulmonary vascular permeability as demonstrated by Evans blue dye assay. Pretreatment of polyP150 in human vascular endothelial cells, HMEC-1 cells, showed inhibition of tumor necrosis factor-α-induced monocytic THP-1 cell adhesion and intercellular adhesion molecule 1/CD54 gene expression. These results suggest that polyP150 ameliorates fatal sepsis by inhibiting expression of the cell adhesion molecule and the accumulation of leukocytes in the vascular endothelium, thereby suppressing the increase in vascular permeability. Our results in this study suggest that polyP150 could be a candidate for novel sepsis treatments.