University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands.
University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands.
Cells. 2021 Jun 29;10(7):1628. doi: 10.3390/cells10071628.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix (ECM) is a core feature of IPF and is likely to affect cell function. We hypothesize that aberrant ECM deposition augments fibroblast senescence, creating a perpetuating cycle favouring disease progression. In this study, primary lung fibroblasts were cultured on control and IPF-derived ECM from fibroblasts pretreated with or without profibrotic and prosenescent stimuli, and markers of senescence, fibrosis-associated gene expression and secretion of cytokines were measured. Untreated ECM derived from control or IPF fibroblasts had no effect on the main marker of senescence p16 and p21. However, the expression of alpha smooth muscle actin (ACTA2) and proteoglycan decorin (DCN) increased in response to IPF-derived ECM. Production of the proinflammatory cytokines C-X-C Motif Chemokine Ligand 8 (CXCL8) by lung fibroblasts was upregulated in response to senescent and profibrotic-derived ECM. Finally, the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were upregulated in response to both senescent- and profibrotic-derived ECM. In summary, ECM deposited by IPF fibroblasts does not induce cellular senescence, while there is upregulation of proinflammatory and profibrotic cytokines and differentiation into a myofibroblast phenotype in response to senescent- and profibrotic-derived ECM, which may contribute to progression of fibrosis in IPF.
特发性肺纤维化（IPF）是一种预后不良的肺部疾病，其生存状况较差。年龄是一个主要的危险因素，在这种疾病中，肺泡上皮细胞和肺成纤维细胞都表现出细胞衰老的特征，这是衰老的一个标志。纤维细胞外基质（ECM）的积累是 IPF 的一个核心特征，可能会影响细胞功能。我们假设异常的 ECM 沉积会加剧成纤维细胞衰老，形成一个有利于疾病进展的持续循环。在这项研究中，我们将原代肺成纤维细胞培养在对照和 IPF 衍生的 ECM 上，这些 ECM 来自于用或不用促纤维化和促衰老刺激物预处理的成纤维细胞，测量衰老标志物、纤维化相关基因表达和细胞因子的分泌。未经处理的对照或 IPF 成纤维细胞来源的 ECM 对衰老的主要标志物 p16 和 p21 没有影响。然而，α平滑肌肌动蛋白（ACTA2）和蛋白聚糖decorin（DCN）的表达在 IPF 衍生的 ECM 中增加。肺成纤维细胞产生的促炎细胞因子 C-X-C 基序趋化因子配体 8（CXCL8）对衰老和促纤维化衍生的 ECM 呈上调表达。最后，转化生长因子β1（TGF-β1）和结缔组织生长因子（CTGF）这两种促纤维化细胞因子对衰老和促纤维化衍生的 ECM 的反应均上调。总之，IPF 成纤维细胞沉积的 ECM 不会诱导细胞衰老，而对衰老和促纤维化衍生的 ECM 的反应是促炎和促纤维化细胞因子的上调以及向肌成纤维细胞表型的分化，这可能有助于 IPF 中纤维化的进展。
Zotero 插件
