Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis.
Sepsis is a complex, incompletely understood and often fatal disorder, typically accompanied by hypotension, that is considered to represent a dysregulated host response to infection. Neurotensin (NT) is a 13-amino-acid peptide that, among its multiple effects, induces hypotension. We find that intraperitoneal and plasma concentrations of NT are increased in mice after severe cecal ligation and puncture (CLP), a model of sepsis, and that mice treated with a pharmacological antagonist of NT, or NT-deficient mice, show reduced mortality during severe CLP. In mice, mast cells can degrade NT and reduce NT-induced hypotension and CLP-associated mortality, and optimal expression of these effects requires mast cell expression of neurotensin receptor 1 and neurolysin. These findings show that NT contributes to sepsis-related mortality in mice during severe CLP and that mast cells can lower NT concentrations, and suggest that mast cell-dependent reduction in NT levels contributes to the ability of mast cells to enhance survival after CLP.
Piliponsky
Adrian M
AM
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Chen
Ching-Cheng
CC
Nishimura
Toshihiko
T
Metz
Martin
M
Rios
Eon J
EJ
Dobner
Paul R
PR
Wada
Etsuko
E
Wada
Keiji
K
Zacharias
Sherma
S
Mohanasundaram
Uma M
UM
Faix
James D
JD
Abrink
Magnus
M
Pejler
Gunnar
G
Pearl
Ronald G
RG
Tsai
Mindy
M
Galli
Stephen J
SJ
D000818:Animals; D015550:Cell Degranulation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007022:Hypotension / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008407:Mast Cells / Q000378:metabolism* / Q000502:physiology; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009496:Neurotensin / Q000037:antagonists & inhibitors / Q000097:blood / Q000172:deficiency / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D018028:Receptors, Neurotensin / Q000378:metabolism; D018805:Sepsis / Q000097:blood / Q000378:metabolism*
D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D019009:Proto-Oncogene Proteins c-kit; D008666:Metalloendopeptidases; C062316:neurolysin