Najari Beidokhti Maliheh, Villalba Nuria, Ma Yonggang, Reynolds Amanda, Villamil Juan Hernandez, Yuan Sarah Y
Department of Molecular Pharmacology and Physiology, University of South Florida, Morsani College of Medicine, 12901 Bruce B. Downs Blvd., Tampa, FL, USA.
Department of Surgery, University of South Florida, Morsani College of Medicine, Tampa, FL, USA.
Geroscience. 2025 Jan 16. doi: 10.1007/s11357-025-01517-9.
Cellular senescence contributes to inflammation and organ dysfunction during aging. While this process is generally characterized by irreversible cell cycle arrest, its morphological features and functional impacts vary in different cells from various organs. In this study, we examined the expression of multiple senescent markers in the lungs of young and aged humans and mice, as well as in mouse lung endothelial cells cultured with a senescence inducer, suberoylanilide hydroxamic acid (SAHA), or doxorubicin (DOXO). We detected increased levels of p21, γH2AX, and SA-β-Gal and decreased Ki-67 and Lamin B1 in aged lungs and senescent lung endothelial cells. Importantly, the expression of senescent markers was associated with an inflammatory response in aged mouse lungs characterized by neutrophil infiltration, increased expression of intercellular adhesion molecule 1 (ICAM-1), and decreased protein levels of VE-cadherin and ZO-1. As the latter two are critical constituents of endothelial cell-cell junctions, we hypothesized that their decreased expression could lead to compromised junction barrier integrity. Indeed, senescent endothelial cells (ECs) exhibited impaired barrier properties, as measured by increased permeability to solutes of small size (3-kD) and albumin (70-kD). When co-cultured with neutrophils, senescent ECs and their supernatant promoted neutrophil chemotaxis and trans-endothelial migration. Taken together, our results suggest that lung EC senescence weakens cell-cell junctions, impairs barrier function, and promotes neutrophil adhesion and migration, which may contribute to the development of inflammation and related pathologies in the lungs during aging.
细胞衰老在衰老过程中会导致炎症和器官功能障碍。虽然这个过程通常以不可逆的细胞周期停滞为特征，但其形态特征和功能影响在来自不同器官的不同细胞中有所不同。在本研究中，我们检测了年轻和老年人类及小鼠肺部，以及用衰老诱导剂辛二酰苯胺异羟肟酸（SAHA）或阿霉素（DOXO）培养的小鼠肺内皮细胞中多种衰老标志物的表达。我们发现老年肺部和衰老的肺内皮细胞中p21、γH2AX和SA-β-Gal水平升高，Ki-67和核纤层蛋白B1水平降低。重要的是，衰老标志物的表达与老年小鼠肺部以中性粒细胞浸润、细胞间黏附分子1（ICAM-1）表达增加以及血管内皮钙黏蛋白（VE-cadherin）和紧密连接蛋白1（ZO-1）蛋白水平降低为特征的炎症反应相关。由于后两者是内皮细胞间连接的关键组成部分，我们推测它们表达的降低可能导致连接屏障完整性受损。事实上，衰老的内皮细胞表现出屏障特性受损，这通过对小分子溶质（3-kD）和白蛋白（70-kD）的通透性增加来衡量。当与中性粒细胞共培养时，衰老的内皮细胞及其上清液促进中性粒细胞趋化和跨内皮迁移。综上所述，我们的结果表明肺内皮细胞衰老会削弱细胞间连接、损害屏障功能并促进中性粒细胞黏附和迁移，这可能有助于衰老过程中肺部炎症及相关病理状况的发展。
