Gianì Fiorenza, Roos Benjamin B, Link Patrick A, Somasundram Bharath, Dresler Sara R, Sciacca Enrico, Vancheri Carlo, Javeed Naureen, Ligresti Giovanni, Tschumperlin Daniel J, Caporarello Nunzia
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States.
Department of Clinical and Experimental Medicine, University of Catania,Catania, Italy.
Am J Physiol Cell Physiol. 2025 Jul 1;329(1):C159-C169. doi: 10.1152/ajpcell.00022.2025. Epub 2025 May 24.
Idiopathic pulmonary fibrosis (IPF) is a fatal, aging-related disease characterized by aberrant lung remodeling and progressive scarring, leading to organ failure and death. Current FDA-approved antifibrotic treatments are unable to reverse established disease, highlighting the need for innovative therapeutic approaches targeting novel pathways and cell types. Mounting evidence, including our own, has recently highlighted the pathogenic role of aging-related endothelial abnormalities, including vascular inflammation and oxidative stress, in the progression of lung fibrosis, offering new therapeutic opportunities to block IPF progression. Unexplored, however, are the modalities to restore vascular abnormalities associated with progressive lung fibrosis, representing a critical gap to effective treatments for IPF. In this study, we demonstrate that circulating extracellular vesicles (cEVs) isolated from young mice are capable of reversing the aging-associated transcriptional alterations of the pulmonary vasculature, reducing transcripts associated with innate immunity, oxidative stress, and senescence, while simultaneously increasing transcripts linked to endothelial identity. Using the bleomycin model of persistent lung fibrosis in aged mice, we then demonstrate that pretreatment with cEVs improves the vascular response to injury and attenuates lung fibrosis progression, as demonstrated by reduced lung collagen content and preserved vascular network and lung architecture. These findings support the efficacy of interventions targeting endothelial aging-associated transcriptional alterations, such as young cEV delivery, in mitigating pulmonary fibrosis progression in animal models of persistent fibrosis and indicate the potential benefits of combined therapies that simultaneously address vascular and nonvascular aspects of IPF. This study demonstrates that circulating extracellular vesicles (cEVs) isolated from young mice reverse the transcriptional alterations of the aged mouse pulmonary vasculature, leading to a more youthful endothelial transcriptional phenotype. As a result of this vascular phenotype, aged mice are protected from bleomycin-induced pulmonary fibrosis. These findings highlight the therapeutic potential of targeting vascular aging to alleviate pulmonary fibrosis.
特发性肺纤维化（IPF）是一种与衰老相关的致命疾病，其特征为异常的肺重塑和进行性瘢痕形成，最终导致器官衰竭和死亡。目前美国食品药品监督管理局（FDA）批准的抗纤维化治疗方法无法逆转已确诊的疾病，这凸显了针对新途径和细胞类型的创新治疗方法的必要性。越来越多的证据，包括我们自己的研究，最近都强调了与衰老相关的内皮异常（包括血管炎症和氧化应激）在肺纤维化进展中的致病作用，为阻止IPF进展提供了新的治疗机会。然而，尚未探索恢复与进行性肺纤维化相关的血管异常的方式，这是IPF有效治疗的一个关键缺口。在本研究中，我们证明从年轻小鼠中分离出的循环细胞外囊泡（cEVs）能够逆转肺血管系统中与衰老相关的转录改变，减少与先天免疫、氧化应激和衰老相关的转录本，同时增加与内皮细胞特征相关的转录本。然后，我们使用老年小鼠的博来霉素诱导持续性肺纤维化模型，证明用cEVs预处理可改善血管对损伤的反应并减轻肺纤维化进展，这表现为肺胶原蛋白含量降低、血管网络和肺结构得以保留。这些发现支持了针对内皮衰老相关转录改变的干预措施（如递送年轻的cEVs）在减轻持续性纤维化动物模型中肺纤维化进展方面的有效性，并表明同时解决IPF血管和非血管方面问题的联合疗法具有潜在益处。本研究表明，从年轻小鼠中分离出的循环细胞外囊泡（cEVs）可逆转老年小鼠肺血管系统的转录改变，从而产生更年轻的内皮转录表型。由于这种血管表型，老年小鼠可免受博来霉素诱导的肺纤维化影响。这些发现凸显了针对血管衰老以减轻肺纤维化治疗潜力。
