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Role of Tumor Necrosis Factor-α in vascular hyporeactivity following endotoxic shock and its mechanism

Zhao, HongLiang MD; Kuang, Lei MD; He, JiaoJiang MD; Zhang, ZiSen MD; Zheng, DanYang MD; Duan, ChenYang MD; Zhu, Yu MD; Wu, Yue MD; Zhang, Jie MD; Peng, XiaoYong MD; Li, BingHu MD; Yang, GuangMing PhD; Li, Tao PhD; Liu, LiangMing MD, PhD

Journal of Trauma and Acute Care Surgery: December 2019 - Volume 87 - Issue 6 - p 1346–1353
doi: 10.1097/TA.0000000000002490
ORIGINAL ARTICLES
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BACKGROUND 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.

METHODS 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 Ca2+ were observed. The mechanisms in TNF-α–induced vascular hyporeactivity were further explored.

RESULTS 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 Ca2+. 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.

CONCLUSION 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.

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.

Submitted: April 16, 2019, Revised: July 21, 2019, Accepted: August 10, 2019, Published online: August 28, 2019.

T.L. and L.L. contributed equally to this work.

Address for reprints: LiangMing Liu, MD, PhD, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University (Army Medical University), Daping, Chongqing 400042, People's Republic of China; email: liangmingliu@yahoo.com; Tao Li, PhD, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University (Army Medical University), Daping, Chongqing 400042, People's Republic of China; email: lt200132@163.com.

Online date: August 29, 2019

© 2019 Lippincott Williams & Wilkins, Inc.