Impact of Toll-like receptor 2 deficiency on survival and neurological function after cardiac arrest: a murine model of cardiopulmonary resuscitation.
BACKGROUND
Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with poor survival rate and neurofunctional outcome. Toll-like receptor 2 (TLR2) plays an important role in conditions of sterile inflammation such as reperfusion injury. Recent data demonstrated beneficial effects of the administration of TLR2-blocking antibodies in ischemia/reperfusion injury. In this study we investigated the role of TLR2 for survival and neurofunctional outcome after CA/CPR in mice.


METHODS
Female TLR2-deficient (TLR2(-/-)) and wild type (WT) mice were subjected to CA for eight min induced by intravenous injection of potassium chloride and CPR by external chest compression. Upon the beginning of CPR, n = 15 WT mice received 5 µg/g T2.5 TLR2 inhibiting antibody intravenously while n = 30 TLR2(-/-) and n = 31 WT controls were subjected to injection of normal saline. Survival and neurological outcome were evaluated during a 28-day follow up period. Basic neurological function, balance, coordination and overall motor function as well as spatial learning and memory were investigated, respectively. In a separate set of experiments, six mice per group were analysed for cytokine and corticosterone serum levels eight hours after CA/CPR.


RESULTS
TLR2 deficiency and treatment with a TLR2 blocking antibody were associated with increased survival (77% and 80% vs. 51% of WT control; both P < 0.05). Neurofunctional performance was less compromised in TLR2(-/-) and antibody treated mice. Compared to WT and antibody treated mice, TLR2(-/-) mice exhibited reduced IL-6 (both P < 0.05) but not IL-1β levels and increased corticosterone plasma concentrations (both P < 0.05).


CONCLUSIONS
Deficiency or functional blockade of TLR2 is associated with increased survival and improved neurofunctional outcome in a mouse model of CA/CPR. Thus, TLR2 inhibition could provide a novel therapeutic approach for reducing mortality and morbidity after cardiac arrest and cardiopulmonary resuscitation.
Clinic for Anaesthesiology and Critical Care Medicine, University Hospital Rostock, Rostock, Germany.
Stefan
S
Bergt
Anne
A
Güter
Andrea
A
Grub
Nana-Maria
NM
Wagner
Claudia
C
Beltschany
Sönke
S
Langner
Andreas
A
Wree
Steve
S
Hildebrandt
Gabriele
G
Nöldge-Schomburg
Brigitte
B
Vollmar
Jan P
JP
Roesner
D000818:Animals; D016887:Cardiopulmonary Resuscitation; D005260:Female; D006323:Heart Arrest / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008817:Mice, Mutant Strains; D051195:Toll-Like Receptor 2 / Q000172:deficiency* / Q000235:genetics
D051195:Toll-Like Receptor 2