Department of Respiratory Medicine, Hannover Medical School, 30625 Hannover, Germany.
Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), 30625 Hannover, Germany.
Cells. 2022 Feb 14;11(4):664. doi: 10.3390/cells11040664.
Fibroblastic foci (FF) are characteristic features of usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) and one cardinal feature thought to represent a key mechanism of pathogenesis. Hence, FF have a high impact on UIP/IPF diagnosis in current guidelines. However, although less frequent, these histomorphological hallmarks also occur in other fibrotic pulmonary diseases. Currently, there is therefore a gap in knowledge regarding the underlying molecular similarities and differences of FF in different disease entities.
In this work, we analyzed the compartment-specific gene expression profiles of FF in IPF and sarcoidosis in order to elucidate similarities and differences as well as shared pathomechanisms. For this purpose, we used laser capture microdissection, mRNA and protein expression analysis. Biological pathway analysis was performed using two different gene expression databases. As control samples, we used healthy lung tissue that was donated but not used for lung transplantation.
Based on Holm Bonferroni corrected expression data, mRNA expression analysis revealed a significantly altered expression signature for 136 out of 760 genes compared to healthy controls while half of these showed a similar regulation in both groups. Immunostaining of selected markers from each group corroborated these results. However, when comparing all differentially expressed genes with the -based expression data, only 2 of these genes were differentially expressed between sarcoidosis and IPF compared to controls, i.e., calcium transport protein 1 () and SMAD specific E3 ubiquitin protein ligase 1 (), both in the sarcoidosis group. Direct comparison of sarcoidosis and IPF did not show any differentially regulated genes independent from the statistical methodology. Biological pathway analysis revealed a number of fibrosis-related pathways pronounced in IPF without differences in the regulatory direction.
These results demonstrate that FF of end-stage IPF and sarcoidosis lungs, although different in initiation, are similar in gene and protein expression, encouraging further studies on the use of antifibrotic agents in sarcoidosis.
纤维母细胞灶（FF）是普通间质性肺炎（UIP）/特发性肺纤维化（IPF）的特征性表现，也是被认为代表发病机制关键机制的一个主要特征。因此，FF 对当前指南中 UIP/IPF 的诊断有很大影响。然而，尽管不太常见，但这些组织形态学特征也出现在其他纤维化性肺部疾病中。目前，因此，对于不同疾病实体中 FF 的潜在分子相似性和差异性，知识上存在空白。
在这项工作中，我们分析了 IPF 和结节病中 FF 的特定隔室的基因表达谱，以阐明相似性和差异性以及共同的发病机制。为此，我们使用了激光捕获显微解剖、mRNA 和蛋白质表达分析。使用两个不同的基因表达数据库进行了生物途径分析。作为对照样本，我们使用了健康的肺组织，这些组织是捐赠的，但未用于肺移植。
基于 Holm Bonferroni 校正的表达数据，与健康对照组相比，136 个基因中有 760 个基因的 mRNA 表达分析显示出明显改变的表达谱，而其中一半基因在两组中表现出相似的调节。来自每个组的选定标记的免疫染色证实了这些结果。然而，当将所有差异表达基因与基于数据库的表达数据进行比较时，与对照组相比，在结节病和 IPF 之间，只有 2 个基因在两组之间表现出差异表达，即钙转运蛋白 1（）和 SMAD 特异性 E3 泛素蛋白连接酶 1（），两者均在结节病组中。结节病和 IPF 之间的直接比较没有显示任何独立于统计方法的差异调节基因。生物途径分析显示了许多纤维化相关途径在 IPF 中明显上调，而调节方向没有差异。
这些结果表明，尽管终末期 IPF 和结节病肺中的 FF 在启动方面不同，但在基因和蛋白质表达方面是相似的，这鼓励进一步研究在结节病中使用抗纤维化药物。
