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Neurokinin-1 Receptor Deficiency Improves Survival in Murine Polymicrobial Sepsis Through Multiple Mechanisms in Aged Mice.

Shock (Augusta, Ga.) (2018-08-11)
Juan R Mella, Arthur F Stucchi, Elizabeth R Duffy, Daniel G Remick
ABSTRACT

Substance P (SP) is a neuropeptide that contributes to a proinflammatory state by binding to the neurokinin 1 receptor (NK-1R). Limiting this interaction has been shown to attenuate the acute inflammation. Our hypothesis was that NK-1R activation would contribute to the morbidity and mortality of sepsis in a model using mice genetically deficient in the NK-1R. To investigate the role of the SP/NK-1R axis in a murine model of sepsis, cecal ligation and puncture (CLP) in NK-1R deficient and wild type (WT) aged mice was performed. Acute inflammation was assessed by measuring circulating cytokines and clinical parameters. Deletion of the NK-1R results in improved survival following CLP (NK-1R knockout mice survival = 100% vs. WT = 14%). A reduction in the inflammatory cytokines interleukin (IL) 6, macrophage inflammatory peptide 2, and IL-1 receptor antagonist, improved hemodynamic parameters, and increased neutrophilia were present in the NK-1R-deficient mice after CLP compared with WT mice. These data confirm the hypothesis that eliminating the SP/NK-1R interaction in a highly lethal murine model of sepsis leads to decreased morbidity and mortality through multiple mechanisms.