Pulmonary Midkine Inhibition Ameliorates Sepsis Induced Lung Injury via ACE/Ang II Pathway

Abstract

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 pulmonary function, as well as the mechanism by which midkine induced lung injury in sepsis. MethodsThe peripheral blood sample of septic patients on admission was obtained and measured for midkine, angiotensin-converting enzyme 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. The lung injury was evaluated, 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 ROS production.ConclusionsMidkine participated in the process of sepsis induced lung injury, which was due to the activation of ACE system and angiotensin II release, triggering ROS production.Trial registration Clinicaltrials.gov NCT02605681. Registered 12 November 2015.