Overwhelming neutrophil activation and oxidative stress significantly contribute to acute respiratory distress syndrome (ARDS) pathogenesis. However, the potential of repurposing ribociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor used clinically in cancer treatment, for treating neutrophilic ARDS remains uncertain. This study illustrated the ability and underlying mechanism of ribociclib for treating ARDS and neutrophilic inflammation. Primary human neutrophils were used to determine the therapeutic effects of ribociclib on respiratory bursts, chemotactic responses, and inflammatory signaling. and analyses were performed to determine the underlying molecular mechanisms. The potential of ribociclib repurposing was evaluated using an ARDS model in lipopolysaccharide (LPS)-primed mice. We found that treatment using ribociclib markedly limited overabundant oxidative stress (reactive oxygen species [ROS]) production and chemotactic responses (integrin levels and adhesion) in activated human neutrophils. Ribociclib was also shown to act as a selective inhibitor of phosphodiesterase 4 (PDE4), thereby promoting the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, leading to the inhibition of extracellular signal-regulated kinase (ERK), c-Jun -terminal kinase (JNK) phosphorylation, and calcium influx. Notably, prophylactic administration and post-treatment with ribociclib ameliorated neutrophil infiltration, lung inflammation, accumulation of oxidative stress, pulmonary destruction, and mortality in mice with LPS-induced ARDS. We demonstrated for the first time that ribociclib serves as a novel PDE4 inhibitor for treating neutrophilic inflammation and ARDS. The repurposing ribociclib and targeting neutrophilic PDE4 offer a potential off-label alternative for treating lung lesions and other inflammatory conditions.

中文翻译：

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Ribociclib 利用磷酸二酯酶 4 抑制治疗中性粒细胞炎症和急性呼吸窘迫综合征

压倒性的中性粒细胞活化和氧化应激显着促进急性呼吸窘迫综合征（ARDS）的发病机制。然而，重新利用 ribociclib（临床上用于癌症治疗的细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 抑制剂）治疗中性粒细胞性 ARDS 的潜力仍不确定。这项研究说明了 ribociclib 治疗 ARDS 和中性粒细胞炎症的能力和潜在机制。原代人中性粒细胞用于确定 ribociclib 对呼吸爆发、趋化反应和炎症信号传导的治疗效果。并进行分析以确定潜在的分子机制。使用脂多糖 (LPS) 引发的小鼠的 ARDS 模型评估了 ribociclib 重新利用的潜力。我们发现，使用 ribociclib 治疗显着限制了活化的人中性粒细胞中过多的氧化应激（活性氧 [ROS]）产生和趋化反应（整合素水平和粘附）。 Ribociclib 还被证明可作为磷酸二酯酶 4 (PDE4) 的选择性抑制剂，从而促进环磷酸腺苷 (cAMP)-蛋白激酶 A (PKA) 通路，从而抑制细胞外信号调节激酶 (ERK)、c -Jun -末端激酶（JNK）磷酸化和钙流入。值得注意的是，预防性给药和瑞博西尼后处理可改善 LPS 诱导的 ARDS 小鼠的中性粒细胞浸润、肺部炎症、氧化应激累积、肺部破坏和死亡率。我们首次证明 ribociclib 作为一种新型 PDE4 抑制剂，可用于治疗中性粒细胞炎症和 ARDS。 ribociclib 的重新利用和靶向中性粒细胞 PDE4 为治疗肺部病变和其他炎症性疾病提供了一种潜在的标签外替代方案。