Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells
Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells
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DOI：
10.1152/ajplung.00097.2010
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发表时间：
2011-03-01
影响因子：
4.9
通讯作者：
Kuwano, Kazuyoshi
中科院分区：
文献类型：
--
作者：
Minagawa, Shunsuke;Araya, Jun;Kuwano, Kazuyoshi
2005年10月26日，李文辉，李文IPF中加速的上皮细胞衰老和SIRT 6在TGF-β诱导的人支气管上皮细胞衰老中的抑制作用美国生理学杂志肺细胞分子生理学300：L391-L401，2011年。首次发表于2010年12月17日; doi：10.1152/ajplung.00097.2010.-具有支气管上皮细胞的重塑气隙的上皮再形成是特发性肺纤维化（IPF）中的突出病理学发现，并且与IPF发病机制有关。最近的研究表明，上皮衰老是IPF发展的风险因素，表明这种上皮再生可能受到细胞衰老加速的影响。在沉默调节蛋白（SIRT）家族中，SIRT 6，一种III类组蛋白脱乙酰酶，已被证明可以拮抗衰老。我们评估了与IPF肺中SIRT 6表达相关的细支气管化衰老。衰老相关的β-半乳糖苷酶染色和p21的免疫组化检测来评估细胞衰老。作为转化生长因子（TGF）-β诱导的异常上皮再生衰老的模型，我们使用原代人支气管上皮细胞（HBEC）。评估HBEC中SIRT 6、p21和白细胞介素（IL）-1 β表达水平以及成纤维细胞中I型胶原表达水平的变化。在IPF肺样本中，在衬有囊性重塑的空气空间的支气管上皮细胞中发现衰老标记物和SIRT 6表达的增加。我们发现，TGF-β通过增加p21表达诱导原代HBEC衰老，而TGF-β也诱导SIRT 6，它不足以抑制细胞衰老。然而，SIRT 6的过表达通过p21的蛋白酶体降解有效地抑制TGF-β诱导的衰老。TGF-β诱导的衰老HBEC分泌增加量的IL-1 β，这足以诱导成纤维细胞中的肌成纤维细胞分化。这些发现表明，加速的上皮衰老通过使异常的上皮-间充质相互作用永久化而在IPF发病机制中起作用，这可以被SIRT 6拮抗。
Minagawa S, Araya J, Numata T, Nojiri S, Hara H, Yumino Y, Kawaishi M, Odaka M, Morikawa T, Nishimura SL, Nakayama K, Kuwano K. Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-beta-induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 300: L391-L401, 2011. First published December 17, 2010; doi:10.1152/ajplung.00097.2010.-Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of IPF, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin (SIRT) family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in IPF lung. Senescence-associated beta-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-beta-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1 beta expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In IPF lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-beta induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-beta also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-beta-induced senescence via proteasomal degradation of p21. TGF-beta-induced senescent HBEC secreted increased amounts of IL-1 beta, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6.