Substance P is a neuropeptide that contributes to a pro-inflammatory state by binding to the neurokinin 1 receptor (NK-1R). Limiting this interaction has been shown to attenuate of 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 in survival following CLP (NK-1R knock out mice = 100% vs wild type = 14%). A reduction in the inflammatory cytokines IL-6, MIP-2, and IL-1RA, improved hemodynamic parameters and increased neutrophilia were present in the NK-1R deficient mice after CLP compared to 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.