Abstract
BackgroundCardiac 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.MethodsFemale 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.ResultsTLR2 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).ConclusionDeficiency 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.
Highlights
Despite many years of laboratory and clinical research, survival rate and neurofunctional outcome following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) remain poor
As an indication for a faster recovery after Cardiac arrest (CA)/CPR the time needed for weaning from mechanical ventilation was significantly reduced in Toll-like receptor 2 (TLR2)-/- mice and antibody treated mice (WT + T2.5) compared to wild type (WT) controls (Table 1)
During the 28 day observation period of the study, TLR2-/-and WT mice subjected to treatment with a TLR2-inhibiting antibody showed increased survival compared to WT controls (77% and 80% vs. 51%; P < 0.05)
Summary
Despite many years of laboratory and clinical research, survival rate and neurofunctional outcome following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) remain poor. Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with poor survival rate and neurofunctional outcome. In this study we investigated the role of TLR2 for survival and neurofunctional outcome after CA/CPR in mice. Upon the beginning of CPR, n = 15 WT mice received 5 μg/g T2.5 TLR2 inhibiting antibody intravenously while n = TLR2-/- and n = WT controls were subjected to injection of normal saline. 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). Conclusion: Deficiency or functional blockade of TLR2 is associated with increased survival and improved neurofunctional outcome in a mouse model of CA/CPR. TLR2 inhibition could provide a novel therapeutic approach for reducing mortality and morbidity after cardiac arrest and cardiopulmonary resuscitation
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