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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.

SUBMITTER: Cho EJ

PROVIDER: S-EPMC4944199 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Zwitterionic chitosan for the systemic treatment of sepsis.

Cho Eun Jung EJ Doh Kyung-Oh KO Park Jinho J Hyun Hyesun H Wilson Erin M EM Snyder Paul W PW Tsifansky Michael D MD Yeo Yoon Y

Scientific reports 20160714

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 th ...[more]

PMID: 27412050

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Project description:Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. Although electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We have previously demonstrated that systemic Tamm-Horsfall protein (THP; uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we showed that the kidney increases circulating THP by enhancing the basolateral release of THP from medullary thick ascending limb cells. In patients with sepsis, changes in circulating THP were positively associated with a critical illness. THP was also found de novo in injured lungs. Genetic ablation of THP in mice led to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo led macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis, and chemotaxis, and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improved survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function, and systemic THP has therapeutic potential in sepsis.NEW & NOTEWORTHY Specific therapies to improve outcomes in sepsis with kidney injury have been limited by an unclear understanding of how kidney injury increases sepsis mortality. Here, we identified Tamm-Horsfall protein, known to protect in ischemic acute kidney injury, as protective in preclinical sepsis models. Tamm-Horsfall protein also increased in clinical sepsis without severe kidney injury and concentrated in injured organs. Further study could lead to novel sepsis therapeutics.

Dataset Information

Zwitterionic chitosan for the systemic treatment of sepsis.

Publications

Zwitterionic chitosan for the systemic treatment of sepsis.

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