Repression of the Equilibrative Nucleoside Transporters Dampens Inflammatory Lung Injury
Repression of the Equilibrative Nucleoside Transporters Dampens Inflammatory Lung Injury
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DOI：
10.1165/rcmb.2012-0457oc
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发表时间：
2013-08-01
影响因子：
6.4
通讯作者：
Rosenberger, Peter
中科院分区：
文献类型：
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作者：
Morote-Garcia, Julio C.;Koehler, David;Rosenberger, Peter
急性肺损伤(ALI)是一种严重的肺部疾病，其特征是低氧血症、严重的肺部炎症和高死亡率。腺苷被认为是一种抗炎信号分子，先前的研究表明，炎症组织中细胞外腺苷浓度增加。腺苷信号是通过平衡的核苷转运体(Ents)从细胞外摄取腺苷进入细胞内而终止的。然而，它们在肺部炎症过程中控制腺苷信号的作用仍不清楚。在体外炎症实验后，我们观察到ENT1和ENT2的抑制与细胞外腺苷摄取的减弱有关。使用短的干扰RNA沉默的实验证实了ENT抑制在炎症过程中提高细胞外腺苷浓度的重要贡献。此外，对ent2启动子的研究表明，NF-kappa B是观察到的ENT抑制的关键调节因子。另外，使用小鼠炎症性肺损伤模型进行的体内实验表明，ENT1和ENT2的药理抑制导致肺屏障功能改善，并减少了急性肺部炎症的迹象。虽然在Ent1(-/-)或Ent2(-/-)小鼠身上的实验表明，在脂多糖诱导的肺损伤中有肺保护作用，但对Ents的骨髓嵌合体的检查指出，Ents的非造血性表达是ALI期间抑制肺部炎症的根本原因。综上所述，这些发现揭示了Ents的转录抑制是急性肺部炎症过程中的一种先天保护性反应。抑制ENTS可作为减轻炎性肺损伤的一种治疗选择。
Acute lung injury (ALI) is a devastating disorder of the lung that is characterized by hypoxemia, overwhelming pulmonary inflammation, and a high mortality in the critically ill. Adenosine has been implicated as an anti-inflammatory signaling molecule, and previous studies showed that extracellular adenosine concentrations are increased in inflamed tissues. Adenosine signaling is terminated by the uptake of adenosine from the extracellular into the intracellular compartment via equilibrative nucleoside transporters (ENTs). However, their role in controlling adenosine signaling during pulmonary inflammation remains unknown. After inflammatory in vitro experiments, we observed a repression of ENT1 and ENT2 that was associated with an attenuation of extracellular adenosine uptake. Experiments using short, interfering RNA silencing confirmed a significant contribution of ENT repression in elevating extracellular adenosine concentrations during inflammation. Furthermore, an examination of the ENT2 promoter implicated NF-kappa B as a key regulator for the observed ENT repression. Additional in vivo experiments using a murine model of inflammatory lung injury showed that the pharmacological inhibition of ENT1 and ENT2 resulted in improved pulmonary barrier function and reduced signs of acute inflammation of the lung. Whereas experiments on Ent1(-/-) or Ent2(-/-) mice revealed lung protection in LPS-induced lung injury, an examination of bone marrow chimeras for ENTs pointed to the nonhematopoetic expression of ENTs as the underlying cause of dampened pulmonary inflammation during ALI. Taken together, these findings reveal the transcriptional repression of ENTs as an innate protective response during acute pulmonary inflammation. The inhibition of ENTs could be pursued as a therapeutic option to ameliorate inflammatory lung injury.