Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
Ocul Surf. 2024 Apr;32:198-210. doi: 10.1016/j.jtos.2024.03.006. Epub 2024 Mar 16.
Aging is a well-established risk factor for meibomian gland dysfunction (MGD). We previously reported an accelerated cellular senescence phenomenon in the lacrimal glands of a murine model of chronic graft-versus-host disease (cGVHD). Herein, we aimed to elucidate the relationship between cellular senescence and MGD in cGVHD mice, utilizing the senolytic agent ABT-263.
A cGVHD mouse model was established through allogeneic bone marrow transplantation (BMT) from B10.D2 to BALB/c mice. Subsequently, cGVHD mice were treated with either ABT-263 or vehicle. The eyelids of recipients were analyzed at 4-week intervals post-BMT in both groups.
Meibomian gland (MG) area was significantly smaller in cGVHD mice than in syngeneic control mice. ABT-263-treated mice retained a significantly larger MG area than their vehicle-treated counterparts. Pathological and immunohistochemical examinations revealed significant reductions in eyelid tissue inflammation and pathological fibrosis in the ABT-263 group compared to that in the vehicle-treated group. Additionally, expression of DNA damage markers, senescent cell markers, and senescence-associated secretory phenotype (SASP) factors was elevated in the eyelids of cGVHD mice compared with that in syngeneic mice. The expression of these cellular senescence-associated molecules was considerably suppressed in ABT-263-treated eyelids compared to that in vehicle-treated ones.
Cellular senescence, along with expression of SASP factors, exhibited increased activity in the eyelids, particularly in the MGs of cGVHD mice. ABT-263 mitigated the severity of MGD. These findings highlight the potential of targeting cellular senescence as an effective approach for MGD treatment in cGVHD.
衰老是导致睑板腺功能障碍（MGD）的一个明确的危险因素。我们之前报道过在慢性移植物抗宿主病（cGVHD）的小鼠模型的泪腺中存在加速的细胞衰老现象。在此，我们旨在利用细胞溶解剂 ABT-263 阐明 cGVHD 小鼠中细胞衰老与 MGD 之间的关系。
通过异基因骨髓移植（BMT）从 B10.D2 到 BALB/c 小鼠建立 cGVHD 小鼠模型。随后，用 ABT-263 或载体对 cGVHD 小鼠进行处理。在两组中，在 BMT 后每隔 4 周分析受体的眼睑。
cGVHD 小鼠的睑板腺（MG）面积明显小于同基因对照小鼠。与载体处理的小鼠相比，用 ABT-263 处理的小鼠保留的 MG 面积明显更大。病理和免疫组织化学检查显示，与载体处理组相比，ABT-263 组的眼睑组织炎症和病理性纤维化显著减少。此外，与同基因小鼠相比，cGVHD 小鼠的眼睑中 DNA 损伤标志物、衰老细胞标志物和衰老相关分泌表型（SASP）因子的表达显著升高。与载体处理的眼睑相比，ABT-263 处理的眼睑中这些与细胞衰老相关的分子的表达显著受到抑制。
细胞衰老以及 SASP 因子的表达在 cGVHD 小鼠的眼睑中表现出较高的活性，特别是在 MGs 中。ABT-263 减轻了 MGD 的严重程度。这些发现强调了靶向细胞衰老作为治疗 cGVHD 中 MGD 的有效方法的潜力。
