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.

目的探讨αCGRP（Calca）缺乏是否会加重肺纤维化（PF）。 回顾性分析PF 患者 ( n = 52) 的临床数据。使用免疫组织化学、RNA-seq 和 UPLC-MS/MS 代谢组学分析，将博来霉素 (BLM) 诱导的大鼠模型的肺组织与Calca敲除 (KO) 和野生型 (WT) 的肺组织进行比较。结果表明，PF 患者中检测到 αCGRP 表达下降和 2 型免疫反应激活。在 BLM 诱导的大鼠和Calca -KO 大鼠中，αCGRP 缺乏会增强 AEC 的凋亡并诱导 M2 巨噬细胞。RNA-seq 鉴定了Calca中参与核易位和免疫系统疾病的途径富集-KO大鼠与WT相比。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。Calca -KO 大鼠的转录组和代谢组数据集中 PPAR 通路信号均显着诱导，免疫荧光分析证实 BLM 处理和Calca -KO 大鼠中 PPARγ 的核转位与细胞质和细胞核部分中的 STAT6 定位同步。总之，αCGRP 对 PF 具有保护作用，αCGRP 缺陷可能通过激活 PPARγ 途径促进巨噬细胞的 M2 极化，从而激活 2 型免疫反应并加速 PF 的发展。