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Published on: May 21, 2018
Pulmonary midkine inhibition ameliorates sepsis induced lung injury
Jing-Yuan Xu1, Wei Chang1, Qin Sun1
1Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao Rd., Nanjing, 210009, People's Republic of China.
Background:
Midkine 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.
Methods:
The 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.
Results:
Plasma 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.
Conclusions:
Midkine 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 registration Clinicaltrials.gov NCT02605681. Registered 12 November 2015.
Insights
Midkine levels increase in sepsis and lung injury, associated with the ACE system. Inhibiting midkine may treat sepsis-induced lung injury via the ACE/Angiotensin II pathway.
Area of Science:
- Biochemistry
- Pathology
- Molecular Biology
Background:
- Midkine is a multifunctional molecule involved in critical pathological processes.
- Sepsis is a life-threatening condition characterized by a dysregulated host response to infection.
- Lung injury is a common and severe complication of sepsis.
Purpose of the Study:
- To evaluate midkine level changes in sepsis.
- To investigate the association between midkine and the angiotensin-converting enzyme (ACE) system in sepsis.
- To elucidate the mechanism of midkine-induced sepsis and lung injury.
Main Methods:
- Measured midkine, ACE, and angiotensin II in septic patients.
- Utilized a cecal ligation and puncture (CLP) mouse model for sepsis induction.
- Employed adeno-associated virus (AAV) for targeted midkine expression modulation in lung tissue.
- Conducted in vitro studies using receptor inhibitors to explore midkine's mechanism on ACE system and vascular endothelial cells.
Main Results:
- Plasma midkine levels were significantly elevated in sepsis and correlated with the ACE system.
- Both circulating and lung midkine increased in CLP mice, linked to severe lung injury.
- Regional midkine inhibition in lung tissue via AAV attenuated acute lung injury in the CLP model.
- In vitro studies revealed Notch 2 mediates midkine-induced ACE system activation and angiotensin II release, leading to vascular endothelial injury via reactive oxygen species.
Conclusions:
- Midkine inhibition ameliorates sepsis-induced lung injury.
- The therapeutic effect may involve the ACE/Angiotensin II pathway.
- Notch 2 plays a role in midkine-stimulated ACE activation.
