Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe, Japan.
Transplantation. 2022 Jun 1;106(6):1159-1169. doi: 10.1097/TP.0000000000003987. Epub 2022 May 23.
Lung ischemia-reperfusion injury (IRI) is a form of acute lung injury characterized by nonspecific alveolar damage and lung edema due to robust inflammation. Little is known about the roles of specialized proresolving lipid mediators (SPMs) in lung IRI. Therefore, we aimed to evaluate the dynamic changes in endogenous SPMs during the initiation and resolution of lung IRI and to determine the effects of SPM supplementation on lung IRI.
We used a rat left hilar clamp model with 90 min of ischemia, followed by reperfusion. Dynamic changes in endogenous SPMs were evaluated using liquid chromatography-tandem mass spectrometry.
Endogenous SPMs in the left lung showed a decreasing trend after 1 h of reperfusion. Oxygenation improved between 3 and 7 d following reperfusion; however, the level of endogenous SPMs remained low compared with that in the naïve lung. Among SPM receptors, only formyl peptide receptor type 2 (ALX/FPR2) gene expression in the left lung was increased 3 h after reperfusion, and the inflammatory cells were immunohistochemically positive for ALX/FPR2. Administration of aspirin-triggered (AT) resolvin D1 (AT-RvD1) and AT lipoxin A4 (AT-LXA4), which are agonistic to ALX/FPR2, immediately after reperfusion improved lung function, reduced inflammatory cytokine levels, attenuated lung edema, and decreased neutrophil infiltration 3 h after reperfusion. The effects of AT-RvD1 and AT-LXA4 were not observed after pretreatment with the ALX/FPR2 antagonist.
The level of intrapulmonary endogenous SPMs decreased during lung IRI process and the administration of AT-RvD1 and AT-LXA4 prevented the exacerbation of lung injury via ALX/FPR2.
肺缺血再灌注损伤（IRI）是一种急性肺损伤形式，其特征为非特异性肺泡损伤和肺水肿，这是由于强烈的炎症反应。关于特殊的促解决脂质介质（SPM）在肺 IRI 中的作用知之甚少。因此，我们旨在评估肺 IRI 发生和解决过程中内源性 SPM 的动态变化，并确定 SPM 补充对肺 IRI 的影响。
我们使用大鼠左肺门夹闭模型，夹闭 90 分钟后再灌注。使用液相色谱-串联质谱法评估内源性 SPM 的动态变化。
再灌注 1 小时后，左肺内源性 SPM 呈下降趋势。再灌注 3 至 7 天后氧合改善；然而，与正常肺相比，内源性 SPM 水平仍然较低。在 SPM 受体中，只有左肺中 Formyl Peptide Receptor Type 2（ALX/FPR2）基因表达在再灌注 3 小时后增加，并且炎症细胞的 ALX/FPR2 免疫组织化学阳性。再灌注后立即给予阿司匹林触发的（AT）Resolvin D1（AT-RvD1）和 AT 脂氧素 A4（AT-LXA4），这两种物质都对 ALX/FPR2 具有激动作用，可改善肺功能，降低炎症细胞因子水平，减轻肺水肿，并减少再灌注 3 小时后的中性粒细胞浸润。在用 ALX/FPR2 拮抗剂预处理后，未观察到 AT-RvD1 和 AT-LXA4 的作用。
肺 IRI 过程中肺内内源性 SPM 水平降低，AT-RvD1 和 AT-LXA4 的给药通过 ALX/FPR2 防止了肺损伤的加重。
