Defective autophagy impairs ATF3 activity and worsens lung injury during endotoxemia
Defective autophagy impairs ATF3 activity and worsens lung injury during endotoxemia
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DOI：
10.1007/s00109-014-1132-7
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发表时间：
2014-06-01
影响因子：
4.7
通讯作者：
Albaiceta, Guillermo M.
中科院分区：
文献类型：
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作者：
Aguirre, Alina;Lopez-Alonso, Ines;Albaiceta, Guillermo M.
自噬已成为炎症反应的关键调节因子。为了检查自噬在内毒素血症期间器官功能障碍发展中的作用，用脂多糖攻击野生型和自噬缺陷（Atg4b-null）小鼠。缺乏 Atg4b 的动物在内毒素血症后死亡率增加。在所研究的不同器官中，只有肺部在基因型之间表现出显着差异，突变动物的损伤增加。经过 LPS 处理的野生型小鼠肺部的自噬被激活。同样，当人类支气管细胞暴露于脓毒症患者的血清时，自噬能力增强。我们发现基因敲除小鼠肺部炎症反应增加（中性粒细胞浸润增加，Il6、Il12p40 和 Cxcl2 水平升高），并确定抗炎转录因子 ATF3 的核周隔离是造成基因型差异的推定机制。最后，在暴露 LPS 之前通过饥饿诱导自噬会导致野生型小鼠（而非基因敲除小鼠）对 LPS 的肺部反应减弱。在暴露于 LPS 的人类支气管细胞中也发现了类似的结果。我们的结果证明了自噬在调节肺部对内毒素血症和脓毒症的反应中的核心作用及其通过营养的潜在调节。
Autophagy has emerged as a key regulator of the inflammatory response. To examine the role of autophagy in the development of organ dysfunction during endotoxemia, wild-type and autophagy-deficient (Atg4b-null) mice were challenged with lipopolysaccharide. Animals lacking Atg4b showed increased mortality after endotoxemia. Among the different organs studied, only the lungs showed significant differences between genotypes, with increased damage in mutant animals. Autophagy was activated in lungs from wild-type, LPS-treated mice. Similarly, human bronchial cells show an increased autophagy when exposed to serum from septic patients. We found an increased inflammatory response (increased neutrophilic infiltration, higher levels of Il6, Il12p40, and Cxcl2) in the lungs from knockout mice and identified perinuclear sequestration of the anti-inflammatory transcription factor ATF3 as the putative mechanism responsible for the differences between genotypes. Finally, induction of autophagy by starvation before LPS exposure resulted in a dampened pulmonary response to LPS in wild-type, but not knockout, mice. Similar results were found in human bronchial cells exposed to LPS. Our results demonstrate the central role of autophagy in the regulation of the lung response to endotoxemia and sepsis and its potential modulation by nutrition.