Acute respiratory distress syndrome (ARDS) is a common cause of mortality in patients with acute kidney injury (AKI). Inflammatory crosstalk from the kidney to the lung has been shown to contribute to lung injury after AKI, but anti-inflammatory therapies have not been proven beneficial in human studies. Recently, AKI was shown to alter mitochondria and related metabolic pathways in the heart, but the impact of AKI on lung metabolism has not been investigated to our knowledge. In this study, we evaluated the metabolomic profile of the lung following renal ischemia and reperfusion to identify novel pathways that may be modifiable. We randomized C57BL/6 mice to 20 minutes of bilateral renal arterial clamping or sham operation under ketamine/xylazine anesthesia. At 4 hours after reperfusion, we found a significant increase in markers of lung injury, as well as significant metabolomic changes across lung, kidney, plasma and bronchoalveolar lavage fluid (BALF) compared to shams. Comparative analyses revealed that the fatty acid oxidation pathway was the most significantly altered metabolic pathway, a finding which is consistent with mitochondrial dysfunction systemically and in the lung. These metabolomic changes correlated with the extracellular accumulation of the mitochondrial damage associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA) and transcription factor A, mitochondria (TFAM). Finally, we found that intraperitoneal injection of renal mtDAMPs caused metabolomic changes consistent with mitochondrial dysfunction in the lung in vivo. Mitochondrial function and mtDAMPs warrant further investigation as potential therapeutic targets in preventing lung injury due to AKI.

中文翻译：

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急性肾损伤导致的肺损伤中肺代谢和线粒体 DAMP 的改变

急性呼吸窘迫综合征 (ARDS) 是急性肾损伤 (AKI) 患者死亡的常见原因。从肾脏到肺部的炎症串扰已被证明会导致 AKI 后的肺损伤，但在人体研究中尚未证明抗炎疗法有益。最近，AKI 被证明会改变心脏中的线粒体和相关代谢途径，但据我们所知，AKI 对肺代谢的影响尚未得到研究。在这项研究中，我们评估了肾缺血和再灌注后肺的代谢组学特征，以确定可能可改变的新途径。我们将 C57BL/6 小鼠随机分组，在氯胺酮/甲苯噻嗪麻醉下进行 20 分钟的双侧肾动脉夹闭或假手术。再灌注后 4 小时，我们发现肺损伤标志物显着增加，以及与假手术相比，肺、肾、血浆和支气管肺泡灌洗液 (BALF) 的显着代谢组学变化。比较分析表明，脂肪酸氧化途径是最显着改变的代谢途径，这一发现与全身和肺部的线粒体功能障碍一致。这些代谢组学变化与线粒体损伤相关分子模式 (mtDAMP)、线粒体 DNA (mtDNA) 和转录因子 A、线粒体 (TFAM) 的细胞外积累相关。最后，我们发现腹膜内注射肾 mtDAMPs 引起的代谢组学变化与体内肺线粒体功能障碍一致。线粒体功能和 mtDAMPs 值得进一步研究，作为预防 AKI 引起的肺损伤的潜在治疗靶点。