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Biochem Biophys Res Commun. 2018 Nov 30;506(3):578-584. doi: 10.1016/j.bbrc.2018.10.098. Epub 2018 Oct 23.

Effects of monoacylglycerol lipase inhibitor URB602 on lung ischemia-reperfusion injury in mice.

Author information

1
Department of Anesthesiology, West China Second University Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China.
2
Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China.
3
Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
4
Department of Operation Room, West China Second University Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China.
5
Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: rurongwang@foxmail.com.

Abstract

Lung ischemia-reperfusion injury (LIRI) is a common and severe postoperative pathologic complication that often occurs when the oxygen supply disrupted to the lung tissue fallowed by reperfusion period, in most cases after lung transplantation and cardiopulmonary bypass. Endocannabinoids such as 2-arachidonoylglycerol (2-AG) have very important role as regulators of inflammation. Monoacylglycerol lipase (MAGL) is the main 2-AG-degrading enzyme, and the downstream metabolites of 2-AG play a role in the inflammation. Ischemia reperfusion (IR) was induced by clamping the left pulmonary hilum for 60 min, followed by 120 min of reperfusion in male C57BL/6 mice. Effects of URB602, a MAGL inhibitor, were evaluated in a preventive or therapeutic regimen (5 min before ischemia or reperfusion, respectively). Oxygenation index, wet-to-dry weight ratio and lung injury score were analyzed. Endocannabinoids including 2-AG, anandamide (AEA) and arachidonic acid (AA) levels, metabolites such as Prostaglandin I2 (PGI2), Thromboxane B2 (TXB2) and Leukotrienes B4 (LTB4) and inflammatory markers (Interleukin 6 (IL-6) andTumor necrosis factor-α (TNF-α)) in lung tissues were measured by using mass spectrometry or ELISA analyses. We found that IR increased the wet-to-dry weight ratio of lung and lung injury score and decreased oxygenation index as compared to the sham group. Moreover, treatment with URB602 in preventive or therapeutic regimen reduced the wet-to-dry weight ratio and lung injury score while increased oxygenation index when compared with the IR group, with a more improvement in the preventive regimen group. In addition, treatment with URB602 before ischemia increased 2-AG level but decreased metabolites (AA, PGI2, TXB2, LTB4) and inflammatory markers (IL-6, TNF-α). Thus, our study demonstrated that a pretreatment with URB602 significantly reduced IR-induced lung injury and inflammation. URB602 inhibited LIRI and inflammation by increasing 2-AG level and reducing downstream metabolites from AA to PGI2, TXB2 and LTB4 in lung tissues.

KEYWORDS:

Ischemia reperfusion; Lung injury; Monoacylglycerol lipase

PMID:
30366666
DOI:
10.1016/j.bbrc.2018.10.098
[Indexed for MEDLINE]

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