Almarzooqi Saeeda, Sharma Charu, Saraswathiamma Dhanya, Alsuwaidi Ahmed R, Hadid Noura, Souid Abdul-Kader, Albawardi Alia
Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University United Arab Emirates.
Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University United Arab Emirates.
Am J Transl Res. 2022 Jul 15;14(7):4678-4687. eCollection 2022.
Several and studies have shown that the mammalian target of rapamycin (mTOR) inhibitor sirolimus (rapamycin) suppresses thymus cellular respiration. The objective of this study is to investigate the chronic dose-dependent effects of sirolimus in the thymus. This was monitored using body weight, histomorphology, caspase-3 expression, cytochrome C immunohistochemistry, and cellular bioenergetics as surrogate biomarkers. BALB/c mice received intraperitoneal injections of either sirolimus (2.5, 5, or 10 µg/g) or dimethyl sulfoxide (0.1 µL/g) as a control for 4 weeks. At the end of the treatment, fragments were collected from the thymus, small intestine, adrenal gland, and kidney. They were processed for assessing histologic changes, measuring cellular respiration and ATP levels. Immunohistochemical stain of caspase-3 and cytochrome C was performed on paraffin-embedded tissue. The treated animals exhibited a dose-dependent reduction in weight gain despite adequate food intake. Sirolimus produced significant thymic derangements, manifested by dose-dependent tissue involution, increased cortical apoptotic bodies, increased caspase-3-positive lymphocytes, and increased rate of cellular respiration without a concomitant increase in cellular ATP. There were no similar changes in cellular ATP in the other assessed organs. The effects on thymic cellular bioenergetics suggest mitochondrial derangements, uncoupling of oxidative phosphorylation, and induction of apoptosis.
多项研究表明，雷帕霉素的哺乳动物靶点（mTOR）抑制剂西罗莫司（雷帕霉素）可抑制胸腺细胞呼吸。本研究的目的是调查西罗莫司在胸腺中的慢性剂量依赖性效应。使用体重、组织形态学、半胱天冬酶-3表达、细胞色素C免疫组织化学和细胞生物能量学作为替代生物标志物对其进行监测。BALB/c小鼠腹腔注射西罗莫司（2.5、5或10μg/g）或二甲基亚砜（0.1μL/g）作为对照，持续4周。在治疗结束时，从胸腺、小肠、肾上腺和肾脏收集组织碎片。对其进行处理以评估组织学变化、测量细胞呼吸和ATP水平。对石蜡包埋组织进行半胱天冬酶-3和细胞色素C的免疫组织化学染色。尽管食物摄入量充足，但接受治疗的动物体重增加呈剂量依赖性降低。西罗莫司导致胸腺出现明显紊乱，表现为剂量依赖性组织萎缩、皮质凋亡小体增加、半胱天冬酶-3阳性淋巴细胞增加以及细胞呼吸速率增加，而细胞ATP水平未随之增加。在其他评估器官中，细胞ATP没有类似变化。对胸腺细胞生物能量学的影响表明存在线粒体紊乱、氧化磷酸化解偶联和细胞凋亡诱导。
