Cytochrome P450 Epoxygenase 2J2 Protects Against Lung Ischemia/Reperfusion Injury by Activating the P13K/Akt/GSK-3-β/NF-kB Signaling Pathway During Deep Hypothermic Low Flow in Mice.

Background: Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids, which exert anti-inflammatory effects and alleviate oxidative stress in the cardiovascular system. Our previous work revealed that CYP2J2 is expressed in pulmonary artery endothelial cells. It was therefore hypothesized that CYP2J2 overexpression may prevent lung ischemia/reperfusion injury (LIRI) in 3-week-old C57BL/6 mice during deep hypothermic low flow (DHLF). This study aimed to establish whether CYP2J2 protects against LIRI and the mechanisms of CYP2J2 overexpression during DHLF in mice. The aim of this study was to explore the effects of DHLF on lung tissue in mice and to find out the regularity of this process, so as to provide theoretical data for lung tissue protection in children undergoing this process in clinic.

Methods: A 3-week-old C57BL/6 mouse model was used to mimic LIRI conditions during DHLF by clamping the left pulmonary artery and left main bronchus for 120 min, followed by reperfusion for 2 h. The body temperature of the mice was maintained between 18°C and 19°C to induce DHLF.

Results: During DHLF, lung ischemia/reperfusion increased the left lung wet/dry weight, the left lung weight/body weight ratio, the protein concentration in bronchoalveolar lavage fluid, and the concentration of proinflammatory mediators in the lungs, including interleukin (IL)-1, IL-8, and necrosis factor (NF)-α, and decreased the concentration of the anti-inflammatory mediator IL-10. Furthermore, activation of NF-κB p65 and degradation of IKBα were remarkably increased in lung tissues after ischemia/reperfusion. The CYP2J2 overexpression group showed the opposite results (P < 0.05), and p-Akt1 and p-GSK-3β expression were significantly higher in the CYP2J2 overexpression group (P < 0.05). Moreover, the changes in IL-1, IL-8, tumor necrosis factor-α, IL-10, p-Akt1, p-GSK-3β, NF-κB p65, and IKBα were reversed in the Akt1 gene heterozygous knockout group, and lung damage was significantly higher in the Akt1 gene heterozygous knockout group than in the CYP2J2 overexpression group. CYP2J2 overexpression can protect against LIRI, whereas Akt1 gene heterozygous knockout in mice can abolish this protective effect.

Conclusions: CYP2J2 overexpression can protect against LIRI by activating the P13K/Akt/GSK-3β/NF-kB signaling pathway during DHLF. Thus, changing CYP2J2 expression can be a novel strategy for the prevention and treatment of LIRI during DHLF.