Pharmacologic cholinesterase inhibition improves survival in experimental sepsis.
OBJECTIVE
Lethal sepsis occurs when an excessive inflammatory response evolves that cannot be controlled by physiologic anti-inflammatory mechanisms, such as the recently described cholinergic anti-inflammatory pathway. Here we studied whether the cholinergic anti-inflammatory pathway can be activated by pharmacologic cholinesterase inhibition in vivo.


METHODS
Prospective, randomized laboratory investigation that used an established murine sepsis model.


METHODS
Research laboratory in a university hospital.


METHODS
Female C57BL/6 mice.


METHODS
Sepsis in mice was induced by cecal ligation and puncture. Animals were treated immediately with intraperitoneal injections of nicotine (400 microg/kg), physostigmine (80 microg/kg), neostigmine (80 microg/kg), or solvent three times daily for 3 days.


RESULTS
Treatment with physostigmine significantly reduced lethality (p < or = .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (p < or = .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappaB (p < or = .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 (p < or = .001), and pulmonary neutrophil invasion (p < or = .05). Animals treated with the peripheral cholinesterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals.


CONCLUSIONS
Our results demonstrate that cholinesterase inhibitors can be used successfully in the treatment of sepsis in a murine model and may be of interest for clinical use.
Hofer
Stefan
S
Department of Anaesthesiology, University of Heidelberg, Heidelberg, Germany.
Eisenbach
Christoph
C
Lukic
Ivan K
IK
Schneider
Lutz
L
Bode
Konrad
K
Brueckmann
Martina
M
Mautner
Sven
S
Wente
Moritz N
MN
Encke
Jens
J
Werner
Jens
J
Dalpke
Alexander H
AH
Stremmel
Wolfgang
W
Nawroth
Peter P
PP
Martin
Eike
E
Krammer
Peter H
PH
Bierhaus
Angelika
A
Weigand
Markus A
MA
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009388:Neostigmine / Q000627:therapeutic use*; D009538:Nicotine / Q000627:therapeutic use*; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010830:Physostigmine / Q000627:therapeutic use*; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*
D002800:Cholinesterase Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D018722:Nicotinic Agonists; D009388:Neostigmine; D009538:Nicotine; D010830:Physostigmine