Svobodová Barbora, Löfdahl Anna, Kadefors Måns, Mohamed Ali Salad, Rosmark Oskar, Prabhala Pavan, Magnusson Mattias, Brunnström Hans, Lundin Sofia, Dellgren Göran, Müller Catharina, Elowsson Linda, Westergren-Thorsson Gunilla
Lung Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Lung Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Am J Pathol. 2025 Aug;195(8):1467-1483. doi: 10.1016/j.ajpath.2025.03.013. Epub 2025 Apr 29.
Collagen VII is an essential anchoring protein in the basement membrane zone, maintaining the attachment of stratified and pseudostratified epithelia to the underlying interstitial matrix. However, collagen VII is largely unexplored in normal lungs and idiopathic pulmonary fibrosis (IPF), a disease characterized by excessive accumulation of extracellular matrix and aberrant re-epithelialization of fibrotic lung parenchyma. Analysis of collagen VII protein and mRNA encoded by COL7A1 gene in IPF distal lungs demonstrated elevated levels compared with those in normal lungs. To investigate its cellular source and spatial distribution in lung tissue, immunohistochemistry, RNAscope in situ hybridization, and cell culture experiments, in combination with analysis of public transcriptomic data sets were performed. In the IPF lungs, collagen VII was abundant in pathologically remodeled airways and honeycomb cysts, associated with increased basal cell populations. In contrast, in the control lungs, collagen VII was mainly localized in larger airways. RNA sequencing data revealed that epithelial basal cells and KRT5/KRT17 aberrant basaloid cells are the primary sources of COL7A1 mRNA expression. Furthermore, COL7A1 mRNA was observed in mesenchymal subsets, and both COL7A1 mRNA and the protein were observed in fibroblast foci, another histopathologic feature of IPF. In vitro, COL7A1 mRNA expression was increased in normal human lung fibroblasts treated with transforming growth factor-β1. These findings suggest that collagen VII could be involved in the process of abnormal re-epithelialization in lung fibrosis.
Ⅶ型胶原是基底膜区一种重要的锚定蛋白，维持复层和假复层上皮与下方间质基质的附着。然而，Ⅶ型胶原在正常肺组织和特发性肺纤维化（IPF）中很大程度上未被研究，IPF是一种以细胞外基质过度积聚和纤维化肺实质异常再上皮化为特征的疾病。对IPF远端肺组织中COL7A1基因编码的Ⅶ型胶原蛋白和mRNA分析显示，其水平高于正常肺组织。为了研究其在肺组织中的细胞来源和空间分布，进行了免疫组织化学、RNAscope原位杂交、细胞培养实验，并结合公共转录组数据集进行分析。在IPF肺组织中，Ⅶ型胶原在病理重塑的气道和蜂窝状囊肿中丰富，与基底细胞数量增加有关。相比之下，在对照肺组织中，Ⅶ型胶原主要定位于较大的气道。RNA测序数据显示，上皮基底细胞和KRT5/KRT17异常基底样细胞是COL7A1 mRNA表达的主要来源。此外，在间充质亚群中观察到COL7A1 mRNA，在IPF的另一个组织病理学特征——成纤维细胞灶中同时观察到COL7A1 mRNA和蛋白。在体外，用转化生长因子-β1处理的正常人肺成纤维细胞中COL7A1 mRNA表达增加。这些发现表明，Ⅶ型胶原可能参与肺纤维化中异常再上皮化的过程。
