Department of Cardiovascular Surgical ICU, Tianjin Chest Hospital, Nankai University, Tianjin 300222, P.R. China.
Department of Critical Care Medicine, The Third Central Hospital of Tianjin, Tianjin 300170, P.R. China.
Mol Med Rep. 2021 May;23(5). doi: 10.3892/mmr.2021.11973. Epub 2021 Mar 24.
Sepsis is a life‑threatening organ dysfunction caused by a dysregulated host response to infection, and is a leading cause of mortality worldwide. Myocardial dysfunction is associated with poor prognosis in patients with sepsis and contributes to a high risk of mortality. However, the pathophysiological mechanisms underlying sepsis‑induced myocardial dysfunction are not completely understood. The aim of the present study was to investigate the role of toll‑like receptor 4 (TLR4)/c‑Jun N‑terminal kinase (JNK) signaling in pro‑inflammatory cytokine expression and cardiac dysfunction during lipopolysaccharide (LPS)‑induced sepsis in mice. C57BL/6 mice were pretreated with TAK‑242 or saline for 1 h and then subjected to LPS (12 mg/kg, intraperitoneal) treatment. Cardiac function was assessed using an echocardiogram. The morphological changes of the myocardium were examined by hematoxylin and eosin staining and transmission electron microscopy. The serum protein levels of cardiac troponin I (cTnI) and tumor necrosis factor‑α (TNF‑α) were determined by an enzyme‑linked immunosorbent assay (ELISA). The TLR4 and JNK mRNA levels were analyzed via reverse transcription‑quantitative PCR. TLR4, JNK and phosphorylated‑JNK protein levels were measured by western blotting. In response to LPS, the activation of TLR4 and JNK in the myocardium was upregulated. There were significant increases in the serum levels of TNF‑α and cTnI, as well as histopathological changes in the myocardium and suppressed cardiac function, following LPS stimulation. Inhibition of TLR4 activation using TAK‑242 led to a decrease in the activation of JNK and reduced the protein expression of TNF‑α in plasma, and alleviated histological myocardial injury and improved cardiac function during sepsis in mice. The present data suggested that the TLR4/JNK signaling pathway played a critical role in regulating the production of pro‑inflammatory cytokines and myocardial dysfunction induced by LPS.
脓毒症是一种危及生命的器官功能障碍，由宿主对感染的失调反应引起，是全球死亡的主要原因。心肌功能障碍与脓毒症患者的预后不良相关，并导致高死亡率。然而，脓毒症引起的心肌功能障碍的病理生理机制尚不完全清楚。本研究旨在探讨 Toll 样受体 4（TLR4）/c-Jun N-末端激酶（JNK）信号通路在脂多糖（LPS）诱导的脓毒症小鼠中促炎细胞因子表达和心功能障碍中的作用。C57BL/6 小鼠用 TAK-242 或生理盐水预处理 1 h，然后腹腔注射 LPS（12 mg/kg）。使用超声心动图评估心功能。通过苏木精和伊红染色和透射电镜观察心肌形态变化。通过酶联免疫吸附试验（ELISA）测定血清心肌肌钙蛋白 I（cTnI）和肿瘤坏死因子-α（TNF-α）蛋白水平。通过逆转录-定量 PCR 分析 TLR4 和 JNK mRNA 水平。通过 Western blot 测定 TLR4、JNK 和磷酸化-JNK 蛋白水平。LPS 刺激后，心肌 TLR4 和 JNK 的激活上调。LPS 刺激后，血清 TNF-α和 cTnI 水平显著升高，心肌组织学变化，心功能受到抑制。使用 TAK-242 抑制 TLR4 激活可降低 JNK 的激活，减少血浆中 TNF-α的蛋白表达，并减轻脓毒症小鼠的心肌组织学损伤，改善心功能。这些数据表明，TLR4/JNK 信号通路在调节 LPS 诱导的促炎细胞因子产生和心肌功能障碍方面发挥着关键作用。
