Pulmonary midkine inhibition ameliorates sepsis induced lung injury.

Abstract

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.

• Authors: Jing-Yuan Xu, Wei Chang, Qin Sun, Fei Peng, Yi Yang
• Journal: Journal of translational medicine (J Transl Med) Vol. 19 Issue 1 Pg. 91 (02 27 2021) ISSN: 1479-5876 [Electronic] England
• PMID: 33639987 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Midkine

Topics

• Acute Lung Injury (drug therapy)
• Animals
• Endothelial Cells
• Humans
• Lung
• Mice
• Midkine
• Sepsis (complications, drug therapy)