Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, China; Center of Medical Laboratory, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China.
Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Mol Immunol. 2023 Nov;163:224-234. doi: 10.1016/j.molimm.2023.10.007. Epub 2023 Oct 20.
Cigarette smoke is recognized as a major trigger for individuals with chronic obstructive pulmonary disease (COPD), leading to an amplified inflammatory response. The onset and progression of COPD are affected by multiple environmental and genetic risk factors, such as inflammatory mechanisms, oxidative stress, and an imbalance between proteinase and antiprotease. As a result, conventional drug therapies often have limited effectiveness. This study aimed to investigate the anti-inflammatory effect of sodium butyrate (SB) in COPD and explore its molecular mechanism, thereby deepening our understanding of the potential application of SB in the treatment of COPD. In our study, we observed an increase in the mRNA and protein expressions of inflammatory factors interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), Matrix metallopeptidase 9 (MMP9) and MMP12 in both NR8383 cell and rat models of COPD. However, these expressions were significantly reduced after SB treatment. Meanwhile, SB treatment effectively decreased the phosphorylation levels of nuclear transcription factor-kappa B (NF-κB) p65, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) and inhibited the nuclear translocation of these proteins in the COPD cells, leading to a reduction in the expression of various inflammatory cytokines. Additionally, SB also inhibited the expression level of the Nod-like receptor pyrin domain 3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein (ASC), and Caspase-1 in the cigeratte smoke extract (CSE)-stimulated cells. Our results showed that CSE down-regulated the mRNA levels of G-protein-coupled receptor 43 (GPR43) and GPR109A, while SB only up-regulated the expression of GPR43 and had no effect on GPR109A. Moreover, additional analysis demonstrated that the knockdown of GPR43 diminishes the anti-inflammatory effects of SB. It is evident that siRNA-mediated knockdown of GPR43 prevented the reduction in mRNA expression of IL-1β, IL-6, TNF-α, MMP9, and MMP12, as well as the expression of phosphorylated proteins NF-κB p65, JNK, and p38 MAPKs with SB treatment. These findings revealed a SB/GPR43 mediated pathway essential for attenuating pulmonary inflammatory responses in COPD, which may offer potential new treatments for COPD.
香烟烟雾被认为是导致慢性阻塞性肺疾病（COPD）患者炎症反应加剧的主要诱因。COPD 的发病和进展受到多种环境和遗传风险因素的影响，如炎症机制、氧化应激以及蛋白水解酶和抗蛋白水解酶之间的失衡。因此，传统的药物治疗往往效果有限。本研究旨在探讨丁酸钠（SB）在 COPD 中的抗炎作用及其分子机制，从而加深对 SB 治疗 COPD 潜力的理解。在我们的研究中，我们观察到 NR8383 细胞和 COPD 大鼠模型中炎症因子白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、基质金属蛋白酶 9（MMP9）和基质金属蛋白酶 12（MMP12）的 mRNA 和蛋白表达增加，但 SB 治疗后这些表达显著降低。同时，SB 治疗有效降低了 COPD 细胞中核转录因子-κB（NF-κB）p65、c-Jun N 末端激酶（JNK）和 p38 丝裂原活化蛋白激酶（MAPK）的磷酸化水平，并抑制了这些蛋白的核转位，从而减少了各种炎症细胞因子的表达。此外，SB 还抑制了香烟烟雾提取物（CSE）刺激细胞中 Nod 样受体 pyrin 域 3（NLRP3）炎性体的表达水平，该炎性体由 NLRP3、凋亡相关斑点样蛋白（ASC）和 Caspase-1 组成。我们的结果表明，CSE 下调了 G 蛋白偶联受体 43（GPR43）和 GPR109A 的 mRNA 水平，而 SB 仅上调了 GPR43 的表达，对 GPR109A 没有影响。此外，进一步的分析表明，GPR43 的敲低减弱了 SB 的抗炎作用。显然，siRNA 介导的 GPR43 敲低阻止了 SB 治疗后 IL-1β、IL-6、TNF-α、MMP9 和 MMP12 的 mRNA 表达以及磷酸化蛋白 NF-κB p65、JNK 和 p38 MAPKs 的表达减少。这些发现揭示了 SB/GPR43 介导的途径在 COPD 中减轻肺炎症反应的重要性，这可能为 COPD 提供新的治疗方法。
