Recombinant thrombomodulin prevents acute lung injury induced by renal ischemia-reperfusion injury
Recombinant thrombomodulin prevents acute lung injury induced by renal ischemia-reperfusion injury
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DOI：
10.1038/s41598-019-57205-0
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发表时间：
2020-01-14
影响因子：
4.6
通讯作者：
Morimura, Naoto
中科院分区：
文献类型：
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作者：
Hayase, Naoki;Doi, Kent;Morimura, Naoto
急性肾损伤(AKI)合并急性肺损伤对危重病患者的死亡率有不利影响。最近，一种肾脏缺血再灌注(IR)模型表明，组蛋白和中性粒细胞外陷阱(NETs)参与了肾脏IR后远隔肺损伤的发生。鉴于重组血栓调节蛋白(RTM)通过与循环组蛋白结合而具有抗炎作用，我们的目的是在小鼠双侧肾IR模型上阐明其对AKI所致远隔肺损伤的影响。肾缺血再灌注后2 4h，RTM预处理和延迟治疗均显著降低肺组织髓过氧化物酶活性，但对肾功能无明显影响。此外，RTM还减轻了肾脏IR增强的促炎细胞因子(肿瘤坏死因子-α、白介素6和角质形成细胞衍生的趋化因子)的表达、血管渗漏和肺损伤程度。组蛋白在肾脏和肺中均有大量积聚和活跃的网络形成；然而，RTM仅在肺中显著减少了组蛋白和净积聚。RTM的给药可能通过阻断组蛋白和肺内的净积聚而对肾脏IR后的肺起到保护作用，尽管肾脏没有观察到保护作用。RTM治疗可能是减轻AKI并发远隔肺损伤的辅助策略。
Acute kidney injury (AKI) complicated by acute lung injury has a detrimental effect on mortality among critically ill patients. Recently, a renal ischemia-reperfusion (IR) model suggested the involvement of histones and neutrophil extracellular traps (NETs) in the development of distant lung injury after renal IR. Given that recombinant thrombomodulin (rTM) has anti-inflammatory roles by binding to circulating histones, we aimed to clarify its effect on distant lung injury induced by AKI in a murine bilateral renal IR model. Both pretreatment and delayed treatment with rTM significantly decreased pulmonary myeloperoxidase activity, but they did not affect renal dysfunction at 24 h after renal IR. Additionally, rTM mitigated the renal IR-augmented expression of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, and keratinocyte-derived chemokine), and vascular leakage, as well as the degree of lung damage. Intense histone accumulation and active NET formation occurred in both the kidneys and the lungs; however, rTM significantly decreased the histone and NET accumulation only in the lungs. Administration of rTM may have protective impact on the lungs after renal IR by blocking histone and NET accumulation in the lungs, although no protection was observed in the kidneys. Treatment with rTM may be an adjuvant strategy to attenuate distant lung injury complicating AKI.