Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, 110001, China.
Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, 110122, China.
Respir Res. 2021 Dec 4;22(1):308. doi: 10.1186/s12931-021-01897-4.
Tracheal injury is a common clinical condition that still lacks an effective therapy at present. Stimulation of epithelial sodium channel (ENaC) increases Na transport, which is a driving force to keep tracheal mucosa free edema fluid during tracheal injury. Ferulic acid (FA) has been proved to be effective in many respiratory diseases through exerting anti-oxidant, anti-inflammatory, and anti-thrombotic effects. However, these studies rarely involve the level of ion transport, especially ENaC.
C57BL/J male mice were treated intraperitoneally with normal saline or FA (100 mg/kg) 12 h before, and 12 h after intratracheal administration of lipopolysaccharide (LPS, 5 mg/kg), respectively. The effects of FA on tracheal injury were not only assessed through HE staining, immunofluorescence assay, and protein/mRNA expressions of ENaC located on tracheas, but also evaluated by the function of ENaC in mouse tracheal epithelial cells (MTECs). Besides, to explore the detailed mechanism about FA involved in LPS-induced tracheal injury, the content of cyclic guanosine monophosphate (cGMP) was measured, and Rp-cGMP (cGMP inhibitor) or cGMP-dependent protein kinase II (PKGII)-siRNA (siPKGII) were applied in primary MTECs, respectively.
Histological examination results demonstrated that tracheal injury was obviously attenuated by pretreatment of FA. Meanwhile, FA could reverse LPS-induced reduction of both protein/mRNA expressions and ENaC activity. ELISA assay verified cGMP content was increased by FA, and administration of Rp-cGMP or transfection of siPKGII could reverse the FA up-regulated ENaC protein expression in MTECs.
Ferulic acid can attenuate LPS-induced tracheal injury through up-regulation of ENaC at least partially via the cGMP/PKGII pathway, which may provide a promising new direction for preventive and therapeutic strategy in tracheal injury.
气管损伤是一种常见的临床病症，目前仍缺乏有效的治疗方法。刺激上皮钠离子通道（ENaC）可增加钠转运，这是保持气管损伤时气管黏膜无水肿液的驱动力。阿魏酸（FA）已被证明在许多呼吸系统疾病中通过发挥抗氧化、抗炎和抗血栓作用是有效的。然而，这些研究很少涉及离子转运水平，特别是 ENaC。
C57BL/J 雄性小鼠分别在气管内给予脂多糖（LPS，5mg/kg）前 12 小时和后 12 小时腹腔内给予生理盐水或 FA（100mg/kg）。FA 对气管损伤的影响不仅通过 HE 染色、免疫荧光分析和气管上 ENaC 的蛋白/ mRNA 表达来评估，还通过小鼠气管上皮细胞（MTECs）的 ENaC 功能来评估。此外，为了探讨 FA 参与 LPS 诱导的气管损伤的详细机制，测量了环鸟苷酸（cGMP）的含量，并在原代 MTECs 中分别应用 Rp-cGMP（cGMP 抑制剂）或 cGMP 依赖性蛋白激酶 II（PKGII）-siRNA（siPKGII）。
组织学检查结果表明，FA 预处理明显减轻了气管损伤。同时，FA 可逆转 LPS 诱导的蛋白/ mRNA 表达和 ENaC 活性降低。ELISA 检测证实 FA 增加了 cGMP 的含量，而 Rp-cGMP 或 siPKGII 的给药可逆转 FA 上调 MTECs 中 ENaC 蛋白表达。
阿魏酸可通过 cGMP/PKGII 途径至少部分上调 ENaC 来减轻 LPS 诱导的气管损伤，这可能为气管损伤的预防和治疗策略提供一个有前途的新方向。
