Sordi Regina, Nandra Kiran K, Chiazza Fausto, Johnson Florence L, Cabrera Claudia P, Torrance Hew D, Yamada Noriaki, Patel Nimesh S A, Barnes Michael R, Brohi Karim, Collino Massimo, Thiemermann Christoph
*Centre for Translational Medicine and Therapeutics, Queen Mary University of London, William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, London, UK †Department of Drug Science and Technology, University of Turin, Turin, Italy ‡Department of Clinical Pharmacology, Queen Mary University of London, William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, London, UK §Centre for Trauma Sciences, Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK.
Ann Surg. 2017 Feb;265(2):408-417. doi: 10.1097/SLA.0000000000001664.
To evaluate the effects of artesunate on organ injury and dysfunction associated with hemorrhagic shock (HS) in the rat.
HS is still a common cause of death in severely injured patients and is characterized by impairment of organ perfusion, systemic inflammatory response, and multiple organ failure. There is no specific therapy that reduces organ injury/dysfunction. Artesunate exhibits pharmacological actions beyond its antimalarial activity, such as anticancer, antiviral, and anti-inflammatory effects.
Rats were submitted to HS. Mean arterial pressure was reduced to 30 mm Hg for 90 minutes, followed by resuscitation. Rats were randomly treated with artesunate (2.4 or 4.8 mg/kg i.v.) or vehicle upon resuscitation. Four hours later, parameters of organ injury and dysfunction were assessed.
Artesunate attenuated the multiple organ injury and dysfunction caused by HS. Pathway analysis of RNA sequencing provided good evidence to support an effect of artesunate on the Akt-survival pathway, leading to downregulation of interleukin-1 receptor-associated kinase 1. Using Western blot analysis, we confirmed that treatment of HS rats with artesunate enhanced the phosphorylation (activation) of Protein kinase B (Akt) and endothelial nitric oxide synthase and the phosphorylation (inhibition) of glycogen synthase kinase-3β (GSK-3β). Moreover, artesunate attenuated the HS-induced activation of nuclear factor kappa B and reduced the expression of proinflammatory proteins (inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin 6).
Artesunate attenuated the organ injury/dysfunction associated with HS by a mechanism that involves the activation of the Akt-endothelial nitric oxide synthase survival pathway, and the inhibition of glycogen synthase kinase-3β and nuclear factor kappa B. A phase II clinical trial evaluating the effects of good manufacturing practice-artesunate in patients with trauma and severe hemorrhage is planned.
评估青蒿琥酯对大鼠失血性休克（HS）相关器官损伤和功能障碍的影响。
HS仍是重伤患者常见的死亡原因，其特征为器官灌注受损、全身炎症反应和多器官功能衰竭。目前尚无减少器官损伤/功能障碍的特异性治疗方法。青蒿琥酯除具有抗疟活性外，还表现出其他药理作用，如抗癌、抗病毒和抗炎作用。
对大鼠进行HS处理。将平均动脉压降至30 mmHg并维持90分钟，随后进行复苏。复苏后，大鼠随机接受青蒿琥酯（2.4或4.8 mg/kg静脉注射）或赋形剂治疗。4小时后，评估器官损伤和功能障碍参数。
青蒿琥酯减轻了HS所致的多器官损伤和功能障碍。RNA测序的通路分析提供了充分证据，支持青蒿琥酯对Akt-生存通路有影响，导致白细胞介素-1受体相关激酶1下调。通过蛋白质印迹分析，我们证实用青蒿琥酯治疗HS大鼠可增强蛋白激酶B（Akt）和内皮型一氧化氮合酶的磷酸化（激活）以及糖原合酶激酶-3β（GSK-3β）的磷酸化（抑制）。此外，青蒿琥酯减弱了HS诱导的核因子κB激活，并降低了促炎蛋白（诱导型一氧化氮合酶、肿瘤坏死因子-α和白细胞介素6）的表达。
青蒿琥酯通过激活Akt-内皮型一氧化氮合酶生存通路、抑制糖原合酶激酶-3β和核因子κB的机制减轻了与HS相关的器官损伤/功能障碍。计划开展一项II期临床试验，评估药品生产质量管理规范级青蒿琥酯对创伤和严重出血患者的影响。
