哮喘是一种慢性肺病,在全世界范围内流行。气道壁的结构改变,称为“气道重塑”,被证明是慢性哮喘期间气道功能障碍的核心因素。叉头盒转录因子FOXK2是糖酵解的关键调节因子,与肺纤维化相关的代谢重编程途径。然而,FOXK2在哮喘中的作用有待进一步探讨.在这项研究中,通过卵清蛋白(OVA)致敏和重复OVA攻击诱导慢性哮喘小鼠。FOXK2在OVA小鼠的肺中上调,并且在腺病毒介导的FOXK2沉默后下调。肺部炎症,支气管周围胶原沉积,FOXK2敲低后,OVA小鼠的糖酵解明显减弱。此外,人支气管上皮细胞(BEAS-2B)中FOXK2和SIRT2的表达在TGF-β1刺激后逐渐上调,在FOXK2敲低后下调。此外,FOXK2的功能丧失显著抑制了TGF-β1诱导的BEAS-2B细胞上皮间质转化(EMT)和糖酵解,表现为EMT标记和糖酵解酶的表达改变。糖酵解抑制剂2-脱氧-d-葡萄糖(2-DG)抑制TGF-β1诱导细胞的EMT,使糖酵解成为EMT的驱动力。验证了FOXK2与SIRT2的结合,和SIRT2过表达阻断了FOXK2敲低介导的TGF-β1处理细胞中EMT和糖酵解的抑制,这表明FOXK2以SIRT2依赖性方式调节TGF-β1处理的细胞中的EMT和糖酵解。总的来说,这项研究强调了FOXK2敲低对慢性哮喘气道重塑的保护作用.
Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as \"airway remodeling\", are documented as the core contributor to the airway dysfunction during chronic asthma. Forkhead box transcription factor
FOXK2 is a critical regulator of glycolysis, a metabolic reprogramming pathway linked to pulmonary fibrosis. However, the role of
FOXK2 in asthma waits further explored. In this study, the chronic asthmatic mice were induced via ovalbumin (OVA) sensitization and repetitive OVA challenge.
FOXK2 was upregulated in the lungs of OVA mice and downregulated after adenovirus-mediated
FOXK2 silencing. The lung inflammation, peribronchial collagen deposition, and glycolysis in OVA mice were obviously attenuated after FOXK2 knockdown. Besides, the expressions of FOXK2 and SIRT2 in human bronchial epithelial cells (BEAS-2B) were increasingly upregulated upon TGF-β1 stimulation and downregulated after
FOXK2 knockdown. Moreover, the functional loss of FOXK2 remarkably suppressed TGF-β1-induced epithelial-mesenchymal transition (EMT) and glycolysis in BEAS-2B cells, as manifested by the altered expressions of EMT markers and glycolysis enzymes. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) inhibited the EMT in TGF-β1-induced cells, making glycolysis a driver of EMT. The binding of
FOXK2 to SIRT2 was validated, and SIRT2 overexpression blocked the
FOXK2 knockdown-mediated inhibition of EMT and glycolysis in TGF-β1-treated cells, which suggests that FOXK2 regulates EMT and glycolysis in TGF-β1-treated cells in a SIRT2-dependnet manner. Collectively, this study highlights the protective effect of FOXK2 knockdown on airway remodeling during chronic asthma.