From the State Key Laboratory of Trauma, Burns and Combined Injury, Department 2, Research Institute of Surgery, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing 400042, People's Republic of China.
J Trauma Acute Care Surg. 2019 Dec;87(6):1346-1353. doi: 10.1097/TA.0000000000002490.
Vascular hyporeactivity plays an important role in organ dysfunction induced by endotoxic shock. Given that cytokine, such as TNF-α, plays an important role in endotoxic shock, the aim of the present study is to investigate the role of Tumor Necrosis Factor (TNF)-α in vascular hyporeactivity following endotoxic shock and the mechanisms.
Lipopolysaccharide (LPS) (1 mg/kg) injection was used for replicating the endotoxic shock model in the rabbit. The changes in the level of TNF-α in plasma in the rabbits model and the contractile response of superior mesenteric arteries (SMA) to norepinephrine (NE) and Ca were observed. The mechanisms in TNF-α-induced vascular hyporeactivity were further explored.
The levels of TNF-α in plasma were gradually increased after 1 hour of LPS administration and reached the peak at 6 hours. The contractile responses of SMA to NE were decreased at 1 hour of LPS and lowest at 6 hour. TNF-α (200 ng/mL) incubation decreased contractile response of SMA to NE significantly. Further studies found that calcium desensitization participated in the occurrence of TNF-α-induced vascular hyporeactivity, the changes were consistent with the changes of vascular reactivity, calcium sensitivities were decreased significantly at 1 hour, 2 hours, 4 hours, and 6 hours after LPS injection. TNF-α (200 ng/mL) incubation could significantly reduce the contractile response of SMA to Ca. The activity of Rho-kinase and the changes of myosin light chain 20 (MLC20) phosphorylation level were significantly decreased at 6 hours following LPS administration, and TNF-α (200 ng/mL) incubation led to a decrease of Rho-kinase and MLC20 phosphorylation. Arginine vasopressin significantly antagonized TNF-α (200 ng/mL)-induced the decrease of the vascular reactivity and calcium sensitivity.
TNF-α is involved in vascular hyporeactivity after endotoxic shock. Calcium desensitization plays an important role in TNF-α-induced vascular hyporeactivity after endotoxic shock. Rho-kinase/MLC20 phosphorylation pathway takes part in the regulation of calcium desensitization and vascular hyporeactivity induced by TNF-α. Arginine vasopressin is beneficial to endotoxic shock in TNF-α-induced vascular hyporeactivity.
血管低反应性在内毒素休克引起的器官功能障碍中起重要作用。鉴于细胞因子（如 TNF-α）在内毒素休克中起重要作用，本研究旨在探讨 TNF-α在内毒素休克后血管低反应性中的作用及其机制。
采用脂多糖（LPS）（1mg/kg）注射复制家兔内毒素休克模型。观察家兔模型中血浆 TNF-α水平的变化及肠系膜上动脉（SMA）对去甲肾上腺素（NE）和 Ca 的收缩反应。进一步探讨 TNF-α诱导的血管低反应性的机制。
LPS 给药 1 小时后，血浆 TNF-α水平逐渐升高，6 小时达高峰。LPS 给药 1 小时后 SMA 对 NE 的收缩反应降低，6 小时时最低。TNF-α（200ng/mL）孵育显著降低 SMA 对 NE 的收缩反应。进一步研究发现钙脱敏参与了 TNF-α诱导的血管低反应性的发生，钙敏变化与血管反应性变化一致，LPS 注射后 1 小时、2 小时、4 小时和 6 小时，钙敏显著降低。TNF-α（200ng/mL）孵育可显著降低 SMA 对 Ca 的收缩反应。LPS 给药 6 小时后，Rho-kinase 活性及肌球蛋白轻链 20（MLC20）磷酸化水平明显降低，TNF-α（200ng/mL）孵育导致 Rho-kinase 和 MLC20 磷酸化减少。精氨酸加压素（AVP）显著拮抗 TNF-α（200ng/mL）引起的血管反应性和钙敏降低。
TNF-α参与内毒素休克后血管低反应性。钙脱敏在 TNF-α诱导的内毒素休克后血管低反应性中起重要作用。Rho-kinase/MLC20 磷酸化途径参与 TNF-α诱导的钙脱敏和血管低反应性的调节。精氨酸加压素有利于 TNF-α诱导的内毒素休克后血管低反应性。
