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

• Published in: Shock (Augusta, Ga.) Ga.), 2019-07, Vol.52 (1), p.61-66
• Main Authors: Mella, Juan R, Stucchi, Arthur F, Duffy, Elizabeth R, Remick, Daniel G
• Format: Article
• Language: English
• ISSN: 1073-2322; 1540-0514
• DOI: 10.1097/SHK.0000000000001248

OBJECTIVE: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.