Department of Anatomy and Embryology, Wuhan University Taikang Medical School (School of Basic Medical Sciences), Wuhan, China.
Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
Shock. 2023 May 1;59(5):771-778. doi: 10.1097/SHK.0000000000002104. Epub 2023 Feb 28.
Background: Immunosuppression caused by immune cell apoptosis and an imbalance of T helper 2 cells (T H 2) and T helper 1 cells (T H 1), is associated with poor outcomes in septic patients. Esmolol was reported to improve survival by modulating immune responses in septic shock. Whether esmolol could alleviate sepsis-induced immunosuppression and the optimal dose are unclear. Methods: Four hours after cecal ligation and puncture (CLP), Wistar rats were randomized into CLP, CLP + E-5 (esmolol: 5 mg·kg -1 ·h -1 ) and CLP + E-18 (esmolol: 18 mg·kg -1 ·h -1 ) groups. Eight rats were underwent sham operation. Eighteen hours after CLP, hemodynamics and organ histological injuries were evaluated, peripheral blood mononuclear cells apoptosis and T-lymphocyte subsets counts were determined by flow cytometry, and the expression of p-Akt, Bcl-2, cleaved Caspase-3, and p-Erk1/2 in splenic CD4 + T-lymphocytes was determined by western blot and immunohistochemistry. β 1 -Adrenoreceptor expressions were evaluated using real-time polymerase chain reaction and immunohistochemistry. Results: Cecal ligation and puncture induced tachycardia, hypotension, hyperlactatemia, and multiple organ injury. Heart rate was unchanged in the CLP + E-5 group but decreased in the CLP + E-18 group. Hypotension, lactatemia, and multiple organ injuries were improved only in the CLP + E-5 group. T-lymphocyte apoptosis and T H 2/T H 1 ratio was decreased in CLP + E-5 but not in CLP + E-18. p-Akt and Bcl-2 expressions were increased, while cleaved Caspase-3 and p-Erk1/2 expressions were decreased in CLP + E-5. β 1 -Adrenoreceptor expressions were unchanged in both CLP + E-5 and CLP + E-18 groups. Conclusions: Low dose of esmolol reduced T-lymphocyte apoptosis and restored T H 2/T H 1 ratio in septic shock. Esmolol might modulate Akt/Bcl-2/Caspase-3 pathway to relieve T-lymphocyte apoptosis and inhibit Erk1/2 activity to decrease T H 0 differentiation to T H 2. Esmolol may be a potential immunoregulator of septic shock.
免疫细胞凋亡和辅助性 T 细胞 2 型（T H 2）与辅助性 T 细胞 1 型（T H 1）失衡引起的免疫抑制与脓毒症患者的不良预后相关。已有报道称，依托咪酯通过调节脓毒性休克的免疫反应来改善存活率。然而，依托咪酯是否能够缓解脓毒症引起的免疫抑制以及最佳剂量尚不清楚。
盲肠结扎穿孔（CLP）后 4 小时，Wistar 大鼠被随机分为 CLP 组、CLP+E-5（依托咪酯：5mg·kg -1 ·h -1 ）组和 CLP+E-18（依托咪酯：18mg·kg -1 ·h -1 ）组。其中 8 只大鼠进行假手术。CLP 后 18 小时，评估血流动力学和器官组织损伤情况，通过流式细胞术检测外周血单个核细胞凋亡和 T 淋巴细胞亚群计数，通过 Western blot 和免疫组化检测脾 CD4 + T 淋巴细胞中 p-Akt、Bcl-2、cleaved Caspase-3 和 p-Erk1/2 的表达，采用实时聚合酶链反应和免疫组化评估β 1 -肾上腺素能受体的表达。
盲肠结扎穿孔导致心动过速、低血压、高乳酸血症和多器官损伤。CLP+E-5 组的心率无变化，而 CLP+E-18 组的心率下降。仅在 CLP+E-5 组中，低血压、乳酸血症和多器官损伤得到改善。CLP+E-5 组 T 淋巴细胞凋亡和 T H 2/T H 1 比值降低，但 CLP+E-18 组无变化。CLP+E-5 组 p-Akt 和 Bcl-2 的表达增加，而 cleaved Caspase-3 和 p-Erk1/2 的表达减少。CLP+E-5 和 CLP+E-18 组的β 1 -肾上腺素能受体表达均无变化。
低剂量依托咪酯可减少脓毒性休克时 T 淋巴细胞凋亡并恢复 T H 2/T H 1 比值。依托咪酯可能通过调节 Akt/Bcl-2/Caspase-3 通路来减轻 T 淋巴细胞凋亡，并抑制 Erk1/2 活性以减少 T H 0 向 T H 2 的分化。依托咪酯可能是脓毒性休克的潜在免疫调节剂。
