PDF(Pubmed)
Abstract：
Pulmonary fibrosis is characterized by pathological accumulation of scar tissue in the lung parenchyma. Many of the processes that are implicated in fibrosis, including increased extracellular matrix synthesis, also occur following pneumonectomy (PNX), but PNX instead results in regenerative compensatory growth of the lung. As fibroblasts are the major cell type responsible for extracellular matrix production, we hypothesized that comparing fibroblast responses to PNX and bleomycin (BLM) would unveil key differences in the role they play during regenerative versus fibrotic lung responses. RNA-sequencing was performed on flow-sorted fibroblasts freshly isolated from mouse lungs 14 days after BLM, PNX, or sham controls. RNA-sequencing analysis revealed highly similar biological processes to be involved in fibroblast responses to both BLM and PNX, including TGF-β1 and TNF-α. Interestingly, we observed smaller changes in gene expression after PNX than BLM at Day 14, suggesting that the fibroblast response to PNX may be muted by expression of transcripts that moderate pro-fibrotic pathways. Itpkc, encoding inositol triphosphate kinase C, was a gene uniquely up-regulated by PNX and not BLM. ITPKC overexpression in lung fibroblasts antagonized the pro-fibrotic effect of TGF-β1. RNA-sequencing analysis has identified considerable overlap in transcriptional changes between fibroblasts following PNX and those overexpressing ITPKC.
摘要：
肺纤维化的特征在于肺实质中瘢痕组织的病理性积累。许多与纤维化有关的过程，包括增加的细胞外基质合成，也发生在肺切除术(PNX)后，但PNX反而导致肺的再生代偿性生长。由于成纤维细胞是负责细胞外基质产生的主要细胞类型，我们假设,比较成纤维细胞对PNX和博来霉素(BLM)的反应将揭示它们在再生和纤维化肺反应中的作用的关键差异.在BLM后14天，对新鲜分离自小鼠肺的流式分选成纤维细胞进行RNA测序，PNX,或假对照。RNA测序分析显示高度相似的生物过程参与成纤维细胞对BLM和PNX的反应。包括TGF-β1和TNF-α。有趣的是,在第14天,我们观察到PNX后基因表达的变化小于BLM,这表明成纤维细胞对PNX的反应可能因表达缓和促纤维化途径的转录本而减弱.Itpkc,编码肌醇三磷酸激酶C,是由PNX而不是BLM唯一上调的基因。肺成纤维细胞中ITPKC过表达拮抗TGF-β1的促纤维化作用。RNA测序分析已确定PNX后的成纤维细胞与过表达ITPKC的成纤维细胞之间的转录变化存在相当大的重叠。
