Abstract
Purpose :
Since aging is a well-known risk factor for MGD, and cellular senescence is accelerated in the lacrimal glands of a cGVHD mouse model, we hypothesized that cellular senescence might be related to MGD observed in cGVHD. Herein, we aimed to elucidate the relationship between cellular senescence and MGD in a cGVHD mouse model by using the selnolytic agent ABT-263.
Methods :
Allogeneic bone marrow transplantation from B10.D2. to BALB/c mice was performed to produce mice with cGVHD. As a non-cGVHD control, syngeneic BMT was conducted by transplanting donor cells from BALB/c mice into BALB/c mice. The cGVHD mice were divided into 2 groups, which were treated with ABT-263 or vehicle by gavage once a day for 7 days from day 10 to 16 after BMT. We performed histological investigation, immunohistochemical examination, and quantitative PCR to elucidate the association between cellular senescence and MGD in the cGVHD mice at 4-week timepoints after BMT.
Results :
Topographical results showed that meibomian gland (MG) area (%) in the cGVHD mice was significantly decreased than that in the syngeneic control mice, and the ABT-263-treated cGVHD mice retained significantly larger MG area (%) than the vehicle-treated cGVHD mice. Pathological analysis and immunohistochemical analysis using the inflammatory cell marker CD45 and the myofibroblast marker αSMA showed that inflammation and pathological fibrosis of eyelid tissue, including MGs, were significantly reduced in the ABT-263 group compared to the vehicle-treated group. Senescent cells secrete inflammatory cytokines and chemokines; this condition is termed the senescence-associated secretory phenotype (SASP). Compared with the syngeneic control mice, the expression of the DNA damage marker (γ-H2AX), senescent markers (p16 and p21), and SASP factors (IL-6, IL-8, IL1-β, and CXCL9) were significantly elevated in the eyelid of cGVHD mice. In addition, the expression of these cellular senescence-associated molecules in the eyelid in the ABT-263-treated cGVHD mice were significantly suppressed compared with those in the vehicle-treated cGVHD mice.
Conclusions :
Cellular senescence and the expressions of SASP factors were promoted in the eyelid and MGs of the cGVHD mice, and the senolytic agent ABT-263 attenuated the severity of MGD. These findings suggested that cellular senescence might be effective targets for the treatment of MGD in cGVHD.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.