Division of Pulmonary and Critical Care Medicine, Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States.
Am J Physiol Cell Physiol. 2023 Aug 1;325(2):C483-C495. doi: 10.1152/ajpcell.00239.2023. Epub 2023 Jul 17.
Pulmonary fibrosis comprises a range of chronic interstitial lung diseases (ILDs) that impose a significant burden on patients and public health. Among these, idiopathic pulmonary fibrosis (IPF), a disease of aging, is the most common and most severe form of ILD and is treated largely by lung transplantation. The lack of effective treatments to stop or reverse lung fibrosis-in fact, fibrosis in most organs-has sparked the need to understand causative mechanisms with the goal of identifying critical points for potential therapeutic intervention. Findings from many groups have indicated that repeated injury to the alveolar epithelium-where gas exchange occurs-leads to stem cell exhaustion and impaired alveolar repair that, in turn, triggers the onset and progression of fibrosis. Cellular senescence of alveolar epithelial progenitors is a critical cause of stemness failure. Hence, senescence impairs repair and thus contributes significantly to fibrosis. In this review, we discuss recent evidence indicating that senescence of epithelial progenitor cells impairs alveolar homeostasis and repair creating a profibrotic environment. Moreover, we discuss the impact of senescent alveolar epithelial progenitors, alveolar type 2 (AT2) cells, and AT2-derived transitional epithelial cells in fibrosis. Emerging evidence indicates that transitional epithelial cells are prone to senescence and, hence, are a new player involved in senescence-associated lung fibrosis. Understanding the complex interplay of cell types and cellular regulatory factors contributing to alveolar epithelial progenitor senescence will be crucial to developing targeted therapies to mitigate their downstream profibrotic sequelae and to promote normal alveolar repair. With an aging population, lung fibrotic diseases are becoming a global health burden. Dysfunctional repair of the alveolar epithelium is a key causative process that initiates lung fibrosis. Normal alveolar regeneration relies on functional progenitor cells; however, the senescence of these cells, which increases with age, hinders their ability to contribute to repair. Here, we discuss studies on the control and consequence of progenitor cell senescence in fibrosis and opportunities for research.
肺纤维化包括一系列慢性间质性肺疾病（ILDs），这些疾病给患者和公共卫生带来了巨大负担。其中，特发性肺纤维化（IPF）是一种与衰老相关的疾病，是最常见和最严重的ILD 形式，主要通过肺移植治疗。缺乏有效治疗方法来阻止或逆转肺纤维化——事实上，大多数器官的纤维化——这引发了人们对了解致病机制的需求，以期确定潜在治疗干预的关键点。许多研究小组的研究结果表明，反复损伤发生气体交换的肺泡上皮细胞会导致干细胞耗竭和肺泡修复受损，进而引发纤维化的发生和进展。肺泡上皮祖细胞的细胞衰老（cellular senescence）是干细胞衰竭的一个关键原因。因此，衰老会损害修复，从而对纤维化产生重大影响。在这篇综述中，我们讨论了最近的证据，这些证据表明上皮祖细胞的衰老会损害肺泡稳态和修复，从而创造一个促纤维化的环境。此外，我们还讨论了衰老的肺泡上皮祖细胞、肺泡 2 型（AT2）细胞和 AT2 衍生的过渡型上皮细胞在纤维化中的作用。新出现的证据表明，过渡型上皮细胞容易衰老，因此是与衰老相关的肺纤维化中涉及的一个新角色。了解导致肺泡上皮祖细胞衰老的细胞类型和细胞调节因子的复杂相互作用，对于开发靶向治疗方法来减轻其下游促纤维化后果并促进正常肺泡修复至关重要。随着人口老龄化，肺部纤维化疾病正成为全球健康负担。肺泡上皮的功能障碍修复是引发肺纤维化的关键致病过程。正常肺泡的再生依赖于功能正常的祖细胞；然而，这些细胞的衰老（随着年龄的增长而增加）会阻碍它们修复的能力。在这里，我们讨论了关于祖细胞衰老在纤维化中的控制和后果的研究以及研究机会。
