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.
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.
Authors: Juan R Mella; Evan Chiswick; David Stepien; Rituparna Moitra; Elizabeth R Duffy; Arthur Stucchi; Daniel Remick Journal: Crit Care Med Date: 2017-02 Impact factor: 7.598
Authors: Andrew Rhodes; Laura E Evans; Waleed Alhazzani; Mitchell M Levy; Massimo Antonelli; Ricard Ferrer; Anand Kumar; Jonathan E Sevransky; Charles L Sprung; Mark E Nunnally; Bram Rochwerg; Gordon D Rubenfeld; Derek C Angus; Djillali Annane; Richard J Beale; Geoffrey J Bellinghan; Gordon R Bernard; Jean-Daniel Chiche; Craig Coopersmith; Daniel P De Backer; Craig J French; Seitaro Fujishima; Herwig Gerlach; Jorge Luis Hidalgo; Steven M Hollenberg; Alan E Jones; Dilip R Karnad; Ruth M Kleinpell; Younsuck Koh; Thiago Costa Lisboa; Flavia R Machado; John J Marini; John C Marshall; John E Mazuski; Lauralyn A McIntyre; Anthony S McLean; Sangeeta Mehta; Rui P Moreno; John Myburgh; Paolo Navalesi; Osamu Nishida; Tiffany M Osborn; Anders Perner; Colleen M Plunkett; Marco Ranieri; Christa A Schorr; Maureen A Seckel; Christopher W Seymour; Lisa Shieh; Khalid A Shukri; Steven Q Simpson; Mervyn Singer; B Taylor Thompson; Sean R Townsend; Thomas Van der Poll; Jean-Louis Vincent; W Joost Wiersinga; Janice L Zimmerman; R Phillip Dellinger Journal: Crit Care Med Date: 2017-03 Impact factor: 7.598
Authors: Sergio L Zanotti-Cavazzoni; Massimiliano Guglielmi; Joseph E Parrillo; Tracy Walker; R Phillip Dellinger; Steven M Hollenberg Journal: Intensive Care Med Date: 2008-12-09 Impact factor: 17.440