title: Zwitterionic chitosan for the systemic treatment of sepsis.
abstract: Severe sepsis and septic shock are life-threatening conditions, with Gram-negative organisms responsible for most sepsis mortality. Systemic administration of compounds that block the action of lipopolysaccharide (LPS), a constituent of the Gram-negative outer cell membrane, is hampered by their hydrophobicity and cationic charge, the very properties responsible for their interactions with LPS. We hypothesize that a chitosan derivative zwitterionic chitosan (ZWC), previously shown to suppress the production of pro-inflammatory cellular mediators in LPS-challenged macrophages, will have protective effects in an animal model of sepsis induced by systemic injection of LPS. In this study, we evaluate whether ZWC attenuates the fatal effect of LPS in C57BL/6 mice and investigate the mechanism by which ZWC counteracts the LPS effect using a PMJ2-PC peritoneal macrophage cell line. Unlike its parent compound with low water solubility, intraperitoneally administered ZWC is readily absorbed with no local residue or adverse tissue reaction at the injection site. Whether administered at or prior to the LPS challenge, ZWC more than doubles the animals' median survival time. ZWC appears to protect the LPS-challenged organisms by forming a complex with LPS and thus attenuating pro-inflammatory signaling pathways. These findings suggest that ZWC have utility as a systemic anti-LPS agent.
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.|Department of Physiology, College of Medicine, Yeungnam University, 317-1 Daemyung-dong, Daegu, Korea.
authors.forename: Kyung-Oh
authors.initials: KO
authors.lastname: Doh
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
authors.forename: Jinho
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
authors.forename: Hyesun
authors.initials: H
authors.lastname: Hyun
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Wilson
authors.affiliation: Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, 625 Harrison Street, West Lafayette, IN 47907, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Snyder
authors.affiliation: Department of Pediatrics and the Congenital Heart Center, College of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Tsifansky
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.|Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Yeo
mesh_terms: D000818:Animals; D002460:Cell Line; D054426:Chemokine CXCL2 / Q000276:immunology / Q000378:metabolism; D048271:Chitosan / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D008070:Lipopolysaccharides; D048271:Chitosan; D048051:p38 Mitogen-Activated Protein Kinases