Hummler Julia K, Dapaah-Siakwan Fredrick, Vaidya Ruben, Zambrano Ronald, Luo Siwei, Chen Shaoyi, Kerr Nadine, de Rivero Vaccari Juan Pablo, Keane Robert W, Dietrich W Dalton, Bancalari Eduardo, Young Karen C, Wu Shu
Division of Neonatology, Department of Pediatrics, Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
Neonatology. 2017;111(3):280-288. doi: 10.1159/000450918. Epub 2016 Dec 24.
Inflammatory injury, particularly the production of active interleukin (IL)-1β plays a major role in the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants. The release of active IL-1β is controlled by posttranscriptional modifications of its proform (pro-IL-1β) through the inflammasome. Rac1 is a member of the Rho family of GTPases that regulate the inflammatory process.
This study tested the hypothesis that Rac1 signaling increases inflammasome activation that results in damaging inflammation, and that the inhibition of Rac1 signaling prevents lung injury, by inhibiting inflammasome activation in a newborn rat model of BPD induced by hyperoxia.
Newborn rat pups were exposed to room air or hyperoxia (85% O2) and received daily intraperitoneal injections of placebo (normal saline) or NSC23766, a specific Rac1 inhibitor, for 10 days. The effects on lung inflammation, alveolarization, vascular development, vascular remodeling, right ventricular systolic pressure, and right ventricular hypertrophy (RVH) were then assessed.
Hyperoxia exposure upregulated Rac1 and increased the production of active IL-1β, which was accompanied by increasing expression of the inflammasome. In addition, hyperoxia induced the pathological hallmarks of BPD. However, treatment with NSC23766 significantly decreased inflammasome activation and macrophage infiltration, improved alveolar and vascular development, and reduced pulmonary vascular remodeling and RVH.
These results indicate that Rac1 signaling regulates the expression of the inflammasome and plays a pivotal role in the pathogenesis of hyperoxia-induced neonatal lung injury. Therefore, targeting Rac1 signaling may provide a novel strategy to prevent and treat BPD in preterm infants.
炎症损伤，尤其是活性白细胞介素（IL）-1β的产生，在早产儿支气管肺发育不良（BPD）的发病机制中起主要作用。活性IL-1β的释放通过炎性小体对其前体形式（pro-IL-1β）进行转录后修饰来控制。Rac1是调节炎症过程的GTP酶Rho家族的成员。
本研究验证了以下假设：Rac1信号传导增加炎性小体激活，导致有害炎症，而抑制Rac1信号传导可通过抑制高氧诱导的新生大鼠BPD模型中的炎性小体激活来预防肺损伤。
将新生大鼠幼崽暴露于室内空气或高氧环境（85% O₂）中，并每天腹腔注射安慰剂（生理盐水）或特异性Rac1抑制剂NSC23766，持续10天。然后评估对肺部炎症、肺泡化、血管发育、血管重塑、右心室收缩压和右心室肥厚（RVH）的影响。
高氧暴露上调Rac1并增加活性IL-1β的产生，同时炎性小体的表达也增加。此外，高氧诱导了BPD的病理特征。然而，NSC23766治疗显著降低了炎性小体激活和巨噬细胞浸润，改善了肺泡和血管发育，并减少了肺血管重塑和RVH。
这些结果表明，Rac1信号传导调节炎性小体的表达，并在高氧诱导的新生儿肺损伤发病机制中起关键作用。因此，靶向Rac1信号传导可能为预防和治疗早产儿BPD提供一种新策略。
