School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales , Australia.
Faculty of Health and Medicine, University of Newcastle , Callaghan , Australia.
Am J Physiol Lung Cell Mol Physiol. 2018 Aug 1;315(2):L162-L172. doi: 10.1152/ajplung.00037.2018. Epub 2018 Apr 26.
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause with a median survival of only three years. Little is known about the mechanisms that precede the excessive collagen deposition seen in IPF, but cellular senescence has been strongly implicated in disease pathology. Senescence is a state of irreversible cell-cycle arrest accompanied by an abnormal secretory profile and is thought to play a critical role in both development and wound repair. Normally, once a senescent cell has contributed to wound repair, it is promptly removed from the environment via infiltrating immune cells. However, if immune clearance fails, the persistence of senescent cells is thought to drive disease pathology through their altered secretory profile. One of the major cell types involved in wound healing is fibroblasts, and senescent fibroblasts have been identified in the lungs of patients with IPF and in fibroblast cultures from IPF lungs. The question of what is driving abnormally high numbers of fibroblasts into senescence remains unanswered. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a role in a myriad of processes, including cell-cycle progression, gene transcription, as well as mitochondrial respiration, all of which are dysregulated during senescence. Activation of STAT3 has previously been shown to correlate with IPF progression and therefore is a potential molecular target to modify early-stage senescence and restore normal fibroblast function. This review summarizes what is presently known about fibroblast senescence in IPF and how STAT3 may contribute to this phenotype.
特发性肺纤维化（IPF）是一种原因不明的慢性纤维性间质性肺炎，中位生存时间仅为三年。目前对于 IPF 中所见的过度胶原沉积之前的机制知之甚少，但细胞衰老已被强烈提示与疾病病理学有关。衰老是一种不可逆的细胞周期停滞状态，伴有异常的分泌谱，并被认为在发育和伤口修复中都起着关键作用。正常情况下，一旦衰老细胞为伤口修复做出贡献，它就会被浸润的免疫细胞迅速从环境中清除。然而，如果免疫清除失败，认为衰老细胞的持续存在会通过其改变的分泌谱驱动疾病病理学。参与伤口愈合的主要细胞类型之一是成纤维细胞，在 IPF 患者的肺中和来自 IPF 肺的成纤维细胞培养物中已经鉴定出衰老的成纤维细胞。是什么导致异常数量的成纤维细胞进入衰老仍然没有答案。转录因子信号转导和转录激活因子 3（STAT3）在许多过程中发挥作用，包括细胞周期进展、基因转录以及线粒体呼吸，所有这些过程在衰老过程中都失调。STAT3 的激活先前已被证明与 IPF 的进展相关，因此是一个潜在的分子靶点，可以修饰早期衰老并恢复正常成纤维细胞功能。这篇综述总结了目前关于 IPF 中成纤维细胞衰老的知识，以及 STAT3 如何促成这一表型。
