Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States.
Am J Physiol Cell Physiol. 2023 Sep 1;325(3):C565-C579. doi: 10.1152/ajpcell.00124.2023. Epub 2023 Jul 24.
Idiopathic pulmonary fibrosis (IPF) is an irreversible and fatal lung disease that is primarily found in the elderly population, and several studies have demonstrated that aging is the major risk factor for IPF. IPF is characterized by the presence of apoptosis-resistant, senescent fibroblasts that generate an excessively stiff extracellular matrix (ECM). The ECM profoundly affects cellular functions and tissue homeostasis, and an aberrant ECM is closely associated with the development of lung fibrosis. Aging progressively alters ECM components and is associated with the accumulation of senescent cells that promote age-related tissue dysfunction through the expression of factors linked to a senescence-associated secretary phenotype (SASP). There is growing evidence that SASP factors affect various cell behaviors and influence ECM turnover in lung tissue through autocrine and/or paracrine signaling mechanisms. Since life expectancy is increasing worldwide, it is important to elucidate how aging affects ECM dynamics and turnover via SASP and thereby promotes lung fibrosis. In this review, we will focus on the molecular properties of SASP and its regulatory mechanisms. Furthermore, the pathophysiological process of ECM remodeling by SASP factors and the influence of an altered ECM from aged lungs on the development of lung fibrosis will be highlighted. Finally, recent attempts to target ECM alteration and senescent cells to modulate fibrosis will be introduced. Aging is the most prominent nonmodifiable risk factor for various human diseases including Idiopathic pulmonary fibrosis. Aging progressively alters extracellular matrix components and is associated with the accumulation of senescent cells that promote age-related tissue dysfunction. In this review, we will discuss the pathological impact of aging and senescence on lung fibrosis via senescence-associated secretary phenotype factors and potential therapeutic approaches to limit the progression of lung fibrosis.
特发性肺纤维化（IPF）是一种不可逆转和致命的肺部疾病，主要发生在老年人群中，多项研究表明，衰老是 IPF 的主要危险因素。IPF 的特征是存在抗凋亡、衰老的成纤维细胞，这些细胞会产生过度僵硬的细胞外基质（ECM）。ECM 对细胞功能和组织稳态有深远的影响，异常的 ECM 与肺纤维化的发展密切相关。随着年龄的增长，ECM 成分逐渐发生变化，并与衰老细胞的积累有关，这些细胞通过表达与衰老相关分泌表型（SASP）相关的因子，促进与年龄相关的组织功能障碍。越来越多的证据表明，SASP 因子通过自分泌和/或旁分泌信号机制影响各种细胞行为，并影响肺组织中 ECM 的更新。由于全球预期寿命的增加，阐明衰老如何通过 SASP 影响 ECM 动态和更新，从而促进肺纤维化，这一点非常重要。在这篇综述中，我们将重点介绍 SASP 的分子特性及其调控机制。此外，还将强调 SASP 因子对 ECM 重塑的病理生理过程，以及衰老肺中改变的 ECM 对肺纤维化发展的影响。最后，将介绍最近靶向 ECM 改变和衰老细胞以调节纤维化的尝试。衰老（aging）是包括特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）在内的多种人类疾病的最显著的不可改变的危险因素。随着年龄的增长，细胞外基质（extracellular matrix，ECM）成分逐渐发生变化，并与衰老细胞的积累有关，这些细胞通过表达与衰老相关分泌表型（senescence-associated secretory phenotype，SASP）相关的因子，促进与年龄相关的组织功能障碍。在这篇综述中，我们将讨论衰老和衰老细胞通过 SASP 因子对肺纤维化的病理影响，以及限制肺纤维化进展的潜在治疗方法。
