Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice.
Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice.
复制标题
端粒酶缺陷小鼠中 p53 依赖性和独立机制的肺泡干细胞衰老、凋亡和分化
作者：
Zhang K;Wang L;Hong X;Chen H;Shi Y;Liu Y;Liu J;Liu JP
肺早衰和纤维化如特发性肺纤维化（IPF）发生与DNA损伤反应在端粒酶缺乏的肺。调控肺泡细胞凋亡的分子机制还有待进一步研究。目前的研究表明，自然发生的衰老与DNA损伤反应（DDR）和p53信号通路的激活有关。端粒酶RNA组分（TERC）敲除（KO）引起的端粒酶缺乏不仅加速了TERC KO小鼠的复制性衰老，而且改变了肺泡干细胞（AEC2）的分化和凋亡，并增加了先天免疫自然杀伤（NK）细胞。TERC KO导致AEC2中衰老相关异染色质灶（SAHF）标记物HP1γ、p21、p16和凋亡相关cleaved caspase-3的增加。然而，晚期TERC KO小鼠Trp53 - / -等位基因中肿瘤抑制因子p53的额外缺乏显著减弱了衰老和凋亡标志物的增加。此外，p53缺乏对晚期TERC KO小鼠AEC2中T1α（终末分化AEC1的标记物）基因表达升高无显著影响。这些发现表明，在端粒缩短加速的自然衰老或过早衰老过程中，肺衰老和IPF与肺泡干细胞p53依赖性过早复制衰老、细胞凋亡和p53非依赖性分化一起发展，导致肺衰老相关的低度炎症（SALI）。我们的研究表明，端粒酶缺乏诱导的端粒DDR和SALI在肺老化和IPF中具有自然衰老相关的分子机制。
Pulmonary premature ageing and fibrogenesis as in idiopathic pulmonary fibrosis (IPF) occur with the DNA damage response in lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that naturally occurring ageing is associated with the DNA damage response (DDR) and activation of the p53 signalling pathway. Telomerase deficiency induced by telomerase RNA component (TERC) knockout (KO) accelerates not only replicative senescence but also altered differentiation and apoptosis of the pulmonary alveolar stem cells (AEC2) in association with increased innate immune natural killer (NK) cells in TERC KO mice. TERC KO results in increased senescence-associated heterochromatin foci (SAHF) marker HP1γ, p21, p16, and apoptosis-associated cleaved caspase-3 in AEC2. However, additional deficiency of the tumour suppressor p53 in the Trp53−/− allele of the late generation of TERC KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of T1α (a marker of terminal differentiated AEC1) in AEC2 of the late generation of TERC KO mice. These findings demonstrate that, in natural ageing or premature ageing accelerated by telomere shortening, pulmonary senescence and IPF develop with alveolar stem cell p53-dependent premature replicative senescence, apoptosis, and p53-independent differentiation, resulting in pulmonary senescence-associated low-grade inflammation (SALI). Our studies indicate a natural ageing-associated molecular mechanism of telomerase deficiency-induced telomere DDR and SALI in pulmonary ageing and IPF.
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影响因子：
2.7
作者：
Ramirez, MI;Millien, G;Williams, MC
通讯作者：
Williams, MC
DOI：
10.1164/rccm.200804-550oc
发表时间：
2008-10-01
影响因子：
24.7
作者：
Cronkhite, Jennifer T.;Xing, Chao;Garcia, Christine Kim
通讯作者：
Garcia, Christine Kim
影响因子：
3.7
作者：
Flores I;Blasco MA
通讯作者：
Blasco MA
影响因子：
2.7
作者：
Lv X;Cai Z;Li S
通讯作者：
Li S
影响因子：
16.6
作者：
Chen, Zhiyang;Yi, Weiwei;Ju, Zhenyu
通讯作者：
Ju, Zhenyu