Active transcription in the vascular bed characterizes rapid progression in idiopathic pulmonary fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is the most common manifestation of interstitial lung disease (ILD), with a median survival of 3-5 years after diagnosis. IPF is characterized by progressive fibrosis with the development of fibroblastic foci in the interstitium. Despite the short median survival, there is a striking variance in the clinical course of IPF, but the underlying biological mechanisms remain poorly understood. Here we used spatial transcriptomic analysis of IPF patients characterized as stable or rapid progressors (based on their decline in lung function and loss of forced vital capacity (FVC)), terminal-stage IPF subjects delineated for transplant, and 3 non IPF normal lung tissues (Clear margins from excision for pulmonary hamartoma). We investigated the presence of key transcriptional signatures using spatial transcriptomics (2). Briefly, sequential cuts of lung biopsies were stained with Trichrome, H&E, and immunofluorescently labeled to identify nuclei, fibroblasts (alpha smooth muscle actin, aSMA), and the vascular bed (CD31). Using a combination H&E and immunofluorescent staining, regions of interests (ROIs) were selected for transcriptional analysis. This study suggests a key role of the vascular bed in the progression of IPF, warranting further investigations. These data highlight distinct pathways of crosstalk between the fibroblasts and the vascular bed, which could prove central to the pathophysiology of the disease.特发性肺纤维化（Idiopathic Pulmonary Fibrosis, IPF）是间质性肺疾病（Interstitial Lung Disease, ILD）最常见的临床表现类型，确诊后中位生存期为3~5年。IPF以进行性纤维化为特征，伴随肺间质内成纤维细胞灶的形成。尽管中位生存期较短，IPF的临床病程却存在显著异质性，但其潜在的生物学机制仍未得到充分阐明。 本研究针对经临床表型分为稳定型与快速进展型（基于肺功能下降程度及用力肺活量（Forced Vital Capacity, FVC）的丧失情况）的IPF患者、等待肺移植的终末期IPF受试者，以及3例非IPF正常肺组织（来源于肺错构瘤切除的安全切缘组织）开展空间转录组分析。我们借助空间转录组技术（2）探究了关键转录特征的存在情况。简言之，我们对肺活检连续切片分别进行三色染色、苏木精-伊红（Hematoxylin and Eosin, H&E）染色，并通过免疫荧光标记以识别细胞核、成纤维细胞（α平滑肌肌动蛋白，αSMA）及血管床（CD31）。结合H&E染色与免疫荧光染色结果，我们选取感兴趣区域（Regions of Interest, ROIs）进行转录组分析。 本研究提示血管床在IPF进展中发挥关键作用，值得开展进一步探索。本数据集揭示了成纤维细胞与血管床之间独特的串扰通路，该通路或为该疾病病理生理过程的核心环节。