Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City 37614, Tennessee, USA.
Shock. 2012 Aug;38(2):146-52. doi: 10.1097/SHK.0b013e31825ce0de.
Cardiovascular collapse is the major factor contributing to the mortality of trauma-hemorrhage (T-H) patients. Toll-like receptors (TLRs) play a critical role in T-H-induced cardiac dysfunction. This study evaluated the role of TLR9 agonist, CpG-oligodeoxynucleotide (ODN) 1826, in cardiac functional recovery after T-H. Trauma-hemorrhage was induced in a murine model by soft tissue injury and blood withdrawals from the jugular vein to a mean arterial pressure of 35 ± 5 mmHg. Mice were treated with CpG-ODN 1826 (10 μg/30 g body weight) by intraperitoneal injection 1 h before T-H (n = 5-8/group). Hemodynamic parameters were measured before, during hemorrhage, and at 60 min after T-H. Trauma-hemorrhage significantly decreased the mean arterial pressure and left ventricular pressure compared with sham controls. In contrast, CpG-ODN administration significantly attenuated the decrease in arterial pressure and left ventricular pressure due to T-H. Trauma-hemorrhage markedly decreased myocardial levels of phosphorylated Akt by 57.9%. However, CpG-ODN treatment significantly blunted the decrement in phospho-Akt by activating the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The PI3K inhibitor LY294002 partially abolished CpG-induced cardioprotection, indicating that additional signaling pathways are involved in the protective effect of CpG-ODN after T-H. We observed that CpG-ODN treatment also significantly attenuated the decrease in myocardial phospho-ERK levels after T-H. Inhibition of ERK by U0126 also partially abolished the cardioprotective effect of CpG-ODN after T-H. Our data suggest that CpG-ODN significantly attenuates T-H-induced cardiac dysfunction. The mechanisms involve activation of both PI3K/Akt and ERK signaling pathways. The TLR9 agonist, CpG-ODN 1826, may provide a novel treatment strategy for preventing or managing cardiac dysfunction and enhancing recovery in T-H patients.
心血管崩溃是导致创伤性出血 (T-H) 患者死亡的主要因素。 Toll 样受体 (TLR) 在 T-H 诱导的心脏功能障碍中发挥关键作用。本研究评估了 TLR9 激动剂 CpG-寡脱氧核苷酸 (ODN) 1826 在 T-H 后心脏功能恢复中的作用。通过从颈静脉抽取血液使软组织结构损伤，将小鼠模型诱导为 T-H，使平均动脉压降至 35±5mmHg。在 T-H 前 1 小时通过腹腔内注射用 CpG-ODN 1826 (10μg/30g 体重) 对小鼠进行治疗(n=5-8/组)。在 T-H 之前、期间和之后 60 分钟测量血流动力学参数。与假手术对照组相比，T-H 显著降低了平均动脉压和左心室压力。相反，CpG-ODN 给药显著减轻了 T-H 引起的动脉压和左心室压力下降。T-H 使磷酸化 Akt 的心肌水平降低了 57.9%。然而，CpG-ODN 治疗通过激活磷酸肌醇 3-激酶 (PI3K)/Akt 信号通路，显著减弱了磷酸化 Akt 的减少。PI3K 抑制剂 LY294002 部分消除了 CpG 诱导的心脏保护作用，表明在 T-H 后 CpG-ODN 的保护作用涉及其他信号通路。我们观察到 CpG-ODN 治疗也显著减轻了 T-H 后心肌磷酸化 ERK 水平的降低。用 U0126 抑制 ERK 也部分消除了 T-H 后 CpG-ODN 的心脏保护作用。我们的数据表明，CpG-ODN 显著减轻了 T-H 引起的心脏功能障碍。机制涉及 PI3K/Akt 和 ERK 信号通路的激活。TLR9 激动剂 CpG-ODN 1826 可能为预防或治疗 T-H 患者的心脏功能障碍和增强恢复提供一种新的治疗策略。
