Department of Respiratory Critical Care Medicine, Loudi Central Hospital, Loudi, China.
Biomol Biomed. 2023 Mar 16;23(2):259-270. doi: 10.17305/bjbms.2022.8034.
Cigarette smoke (CS) is the leading cause of chronic obstructive pulmonary disease (COPD), which is characterized by chronic bronchial inflammation and emphysema. Growing evidence supports the hypothesis that dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is critically involved in the pathogenesis of CS-mediated COPD. However, the underlying mechanism remains unclear. Here, we report that supressed CFTR expression is strongly associated with abnormal phospholipid metabolism and increased pulmonary inflammation. In a CS-exposed mouse model with COPD-like symptoms, we found that pulmonary expression of sphingosine kinase 2 (SphK2) and sphingosine-1-phosphate (S1P) secretion were significantly upregulated. Therefore, we constructed a SphK2 gene knockout (SphK2-/-) mouse. After CS exposure for six months, histological lung section staining showed disorganized alveolar structure, increased pulmonary fibrosis, and emphysema-like symptoms in wild-type (WT) mice, which were less pronounced in SphK2-/- mice. Further, SphK2 deficiency also decreased CS-induced pulmonary inflammation, which was reflected by a remarkable reduction in pulmonary infiltration of CD45+CD11b+ neutrophils subpopulation and low levels of IL-6 and IL-33 in bronchial alveolar lavage fluid. However, treatment with S1P receptor agonist suppressed CFTR expression and increased Nf-κB-p65 expression and its nuclear translocation in CS-exposed SphK2-/-mice, which also aggravated small airways fibrosis and pulmonary inflammation. In contrast, inhibition of S1P signaling with the S1P receptor analogue FTY720 rescued CFTR expression, suppressed Nf-κB-p65 expression and nuclear translocation, and alleviated pulmonary fibrosis and inflammation after CS exposure. Our results demonstrate that SphK2-mediated S1P production plays a crucial role in the pathogenesis of CS-induced COPD-like disease by impairing CFTR activity and promoting pulmonary inflammation and fibrosis.
香烟烟雾（CS）是慢性阻塞性肺疾病（COPD）的主要原因，其特征是慢性支气管炎症和肺气肿。越来越多的证据支持这样一种假设，即功能失调的囊性纤维化跨膜电导调节因子（CFTR）在 CS 介导的 COPD 发病机制中起着至关重要的作用。然而，其潜在机制尚不清楚。在这里，我们报告称，CFTR 表达受抑制与异常磷脂代谢和肺部炎症增加密切相关。在具有 COPD 样症状的 CS 暴露小鼠模型中，我们发现肺组织中鞘氨醇激酶 2（SphK2）和鞘氨醇-1-磷酸（S1P）的表达显著上调。因此，我们构建了 SphK2 基因敲除（SphK2-/-）小鼠。CS 暴露六个月后，对野生型（WT）小鼠的肺组织切片染色显示，肺泡结构紊乱，肺纤维化增加，出现肺气肿样症状，而 SphK2-/-小鼠的这些症状则不明显。此外，SphK2 缺乏还降低了 CS 诱导的肺部炎症，这反映在支气管肺泡灌洗液中 CD45+CD11b+中性粒细胞亚群的肺浸润显著减少以及 IL-6 和 IL-33 水平降低。然而，S1P 受体激动剂处理抑制了 CS 暴露的 SphK2-/-小鼠中 CFTR 的表达，并增加了 NF-κB-p65 的表达及其核转位，这也加重了小气道纤维化和肺部炎症。相比之下，用 S1P 受体类似物 FTY720 抑制 S1P 信号可挽救 CFTR 的表达，抑制 NF-κB-p65 的表达和核转位，并在 CS 暴露后缓解肺纤维化和炎症。我们的研究结果表明，SphK2 介导的 S1P 产生通过损害 CFTR 活性和促进肺部炎症和纤维化，在 CS 诱导的 COPD 样疾病发病机制中起着至关重要的作用。
