Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China.
Department of Respiratory and Critical Care Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China.
Genes Immun. 2023 Jun;24(3):139-148. doi: 10.1038/s41435-023-00206-x. Epub 2023 May 25.
In order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n = 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that of Calca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced and Calca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders in Calca-KO rats compared to WT. Mass spectrometry of lung tissue from Calca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets in Calca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated and Calca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.
为了探索 αCGRP（Calca）缺乏是否会加重肺纤维化（PF），对 52 例 PF 患者的临床资料进行了回顾性分析。采用免疫组织化学、RNA-seq 和 UPLC-MS/MS 代谢组学分析比较博来霉素（BLM）诱导的大鼠模型与 Calca 敲除（KO）和野生型（WT）大鼠的肺组织。结果显示，PF 患者中 αCGRP 表达降低，2 型免疫反应被激活。在 BLM 诱导和 Calca-KO 大鼠中，αCGRP 缺乏增强了 AEC 的凋亡并诱导了 M2 巨噬细胞。与 WT 相比，Calca-KO 大鼠的 RNA-seq 鉴定出涉及核易位和免疫系统紊乱的途径富集。Calca-KO 大鼠肺组织的质谱分析显示脂质代谢异常，包括 LTB4、PDX、1-HETE 水平升高。PPAR 通路信号在 Calca-KO 大鼠的转录组和代谢组数据集中均显著诱导，免疫荧光分析证实 BLM 处理和 Calca-KO 大鼠中 PPARγ 的核易位与 STAT6 在细胞质和核部分的定位同步。总之，αCGRP 对 PF 具有保护作用，αCGRP 缺乏促进 M2 极化的巨噬细胞，可能通过激活 PPARγ 通路，激活 2 型免疫反应并加速 PF 发展。
