Department of Medicine, University of Colorado Denver, USA.
Am J Physiol Renal Physiol. 2012 Sep 15;303(6):F864-72. doi: 10.1152/ajprenal.00025.2012. Epub 2012 Jul 11.
Serum IL-6 is increased in patients with acute kidney injury (AKI) and is associated with prolonged mechanical ventilation and increased mortality. Inhibition of IL-6 in mice with AKI reduces lung injury associated with a reduction in the chemokine CXCL1 and lung neutrophils. Whether circulating IL-6 or locally produced lung IL-6 mediates lung injury after AKI is unknown. We hypothesized that circulating IL-6 mediates lung injury after AKI by increasing lung endothelial CXCL1 production and subsequent neutrophil infiltration. To test the role of circulating IL-6 in AKI-mediated lung injury, recombinant murine IL-6 was administered to IL-6-deficient mice. To test the role of CXCL1 in AKI-mediated lung injury, CXCL1 was inhibited by use of CXCR2-deficient mice and anti-CXCL1 antibodies in mice with ischemic AKI or bilateral nephrectomy. Injection of recombinant IL-6 to IL-6-deficient mice with AKI increased lung CXCL1 and lung neutrophils. Lung endothelial CXCL1 was increased after AKI. CXCR2-deficient and CXCL1 antibody-treated mice with ischemic AKI or bilateral nephrectomy had reduced lung neutrophil content. In summary, we demonstrate for the first time that circulating IL-6 is a mediator of lung inflammation and injury after AKI. Since serum IL-6 is increased in patients with either AKI or acute lung injury and predicts prolonged mechanical ventilation and increased mortality in both conditions, our data suggest that serum IL-6 is not simply a biomarker of poor outcomes but a pathogenic mediator of lung injury.
血清白细胞介素 6（IL-6）在急性肾损伤（AKI）患者中升高，与机械通气时间延长和死亡率增加相关。在 AKI 小鼠中抑制 IL-6 可减少与趋化因子 CXCL1 减少和肺中性粒细胞浸润相关的肺损伤。循环中的 IL-6 或局部产生的肺 IL-6 是否介导 AKI 后的肺损伤尚不清楚。我们假设循环中的 IL-6 通过增加肺内皮细胞 CXCL1 的产生和随后的中性粒细胞浸润来介导 AKI 后的肺损伤。为了测试循环中的 IL-6 在 AKI 介导的肺损伤中的作用，将重组鼠 IL-6 给予 IL-6 缺陷型小鼠。为了测试 CXCL1 在 AKI 介导的肺损伤中的作用，在缺血性 AKI 或双侧肾切除的小鼠中使用 CXCR2 缺陷型小鼠和抗 CXCL1 抗体抑制 CXCL1。将重组 IL-6 注射到 AKI 的 IL-6 缺陷型小鼠中，增加了肺 CXCL1 和肺中性粒细胞。AKI 后肺内皮细胞 CXCL1 增加。在缺血性 AKI 或双侧肾切除的 CXCR2 缺陷型和 CXCL1 抗体治疗的小鼠中，肺中性粒细胞含量减少。总之，我们首次证明循环中的 IL-6 是 AKI 后肺炎症和损伤的介质。由于血清 IL-6 在 AKI 或急性肺损伤患者中增加，并预测两种情况下的机械通气时间延长和死亡率增加，我们的数据表明血清 IL-6 不仅是不良预后的生物标志物，而且是肺损伤的致病介质。
