title: Antagonism of the Neurokinin-1 Receptor Improves Survival in a Mouse Model of Sepsis by Decreasing Inflammation and Increasing Early Cardiovascular Function.
abstract: OBJECTIVE
  Sepsis remains a serious clinical problem despite intensive research efforts and numerous attempts to improve outcome by modifying the inflammatory response. Substance P, the principal ligand for the neurokinin-1 receptor, is a potent proinflammatory mediator that exacerbates inflammatory responses and cardiovascular variables in sepsis.
  
  
  METHODS
  The current study examined whether inhibition of the neurokinin-1 receptor with a specific antagonist (CJ-12,255) would improve survival in the cecal ligation and puncture model of sepsis in adult female outbred mice.
  
  
  METHODS
  University basic science research laboratory.
  
  
  RESULTS
  Neurokinin-1 receptor treatment at the initiation of sepsis improved survival in cecal ligation and puncture sepsis (neurokinin-1 receptor antagonist survival = 79% vs vehicle = 54%). Delaying therapy for as little as 8 hours postcecal ligation and puncture failed to provide a survival benefit. Neurokinin-1 receptor antagonist treatment did not prevent the sepsis-induced decrease in circulating WBCs, augment the early (6 hr postcecal ligation and puncture) recruitment of inflammatory cells to the peritoneum, or improve phagocytic cell killing of pathogens. However, the neurokinin-1 receptor antagonist significantly reduced both circulating and peritoneal cytokine concentrations. In addition, the cardiovascular variable, pulse distension (a surrogate for stroke volume) was improved in the neurokinin-1 receptor antagonist group during the first 6 hours of sepsis, and there was a significant reduction in loss of fluid into the intestine.
  
  
  CONCLUSIONS
  These data show that early activation of the neurokinin-1 receptor by substance P decreases sepsis survival through multiple mechanisms including depressing stroke volume, increasing fluid loss into the intestine, and increasing inflammatory cytokine production.
authors.affiliation: All authors: Departments of Surgery and Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Mella
authors.forename: Evan
authors.initials: E
authors.lastname: Chiswick
authors.forename: David
authors.initials: D
authors.lastname: Stepien
authors.forename: Rituparna
authors.initials: R
authors.lastname: Moitra
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Duffy
authors.forename: Arthur
authors.initials: A
authors.lastname: Stucchi
authors.forename: Daniel
authors.initials: D
authors.lastname: Remick
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D007958:Leukocyte Count; D051379:Mice; D008813:Mice, Inbred ICR; D064729:Neurokinin-1 Receptor Antagonists / Q000627:therapeutic use*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: C480026:6-diphenylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-1-azabicyclo(2.2.2)octane-3-carboxylic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1