Pulmonary midkine inhibition ameliorates sepsis induced lung injury

Journal of Translational Medicine

Qin Sun¹  Jing-Yuan Xu¹  Fei Peng¹  Wei Chang¹  Yi Yang¹ 

[1] Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd., 210009, Nanjing, People’s Republic of China;

关键词: Midkine;    Angiotensin converting enzyme;    Sepsis;    Angiotensin II;   

DOI  :  10.1186/s12967-021-02755-z

来源: Springer

【 摘 要 】

BackgroundMidkine is a multi-functional molecule participating in a various key pathological process. We aimed to evaluate the change of midkine in sepsis and its association with angiotensin-converting enzyme (ACE) system, as well as the mechanism by which midkine induced in sepsis and lung injury.MethodsThe peripheral blood sample of septic patients on admission was obtained and measured for midkine, ACE and angiotensin II. Cecal ligation and puncture (CLP) mouse model was used, and adeno-associated virus (AAV) was stilled trans-trachea for regional targeting midkine expression, comparing the severity of lung injury. Furthermore, we studied the in vitro mechanism of midkine activates ACE system by using inhibitors targeting candidate receptors of midkine, and its effects on the vascular endothelial cells.ResultsPlasma midkine was significantly elevated in sepsis, and was closely associated with ACE system. Both circulating and lung midkine was increased in CLP mouse, and was related to severe lung injury. Regional interfering midkine expression in lung tissue by AAV could alleviate acute lung injury in CLP model. In vitro study elucidated that Notch 2 participated in the activation of ACE system and angiotensin II release, induced by midkine and triggered vascular endothelial injury by angiotensin II induced reactive oxygen species production.ConclusionsMidkine inhibition ameliorates sepsis induced lung injury, which might via ACE/Ang II pathway and the participation of Notch 2 in the stimulation of ACE.Trial registrationClinicaltrials.gov NCT02605681. Registered 12 November 2015

【 授权许可】

CC BY