Khaibullina Alfia, Almeida Luis E F, Wang Li, Kamimura Sayuri, Wong Edward C C, Nouraie Mehdi, Maric Irina, Albani Sarah, Finkel Julia, Quezado Zenaide M N
The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
Laboratory Medicine, Children's Research Institute, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
Blood Cells Mol Dis. 2015 Dec;55(4):363-72. doi: 10.1016/j.bcmd.2015.08.001. Epub 2015 Aug 5.
Fetal hemoglobin-inducing therapies are disease-modifying and ameliorate the pain phenotype in sickle cell disease (SCD). Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, increases HbF in erythroid precursor cells in vitro. We hypothesized that rapamycin would increase HbF levels and improve nociception phenotype in SCD mice. We used sine-wave electrical stimulation to examine nocifensive phenotype and evaluate myelinated [2000Hz (Aβ-fiber) and 250Hz (Aδ-fiber)] and unmyelinated (5Hz C-fibers)] sensory fiber function. Rapamycin significantly increased γ-globin mRNA and HbF levels [+2.3% (0.7, 3.9), mean increase (95% confidence interval, CI), p=0.006]. In homozygous (sickling) mice, long- (16 weeks), but not short-term (6 weeks), rapamycin treatment increased 2000Hz and 250Hz current thresholds in a pattern that varied according to sex. In male, but not female mice, rapamycin (compared with vehicle) was associated with increases in 2000Hz [21Units (7, 35), mean difference (95% CI), p=0.009 for sex∗treatment interaction] and 250Hz [9Units (1, 16), p=0.01] current thresholds. In rapamycin-treated homozygotes, HbF levels directly correlated with myelinated [2000Hz(Aβ-fiber, r=0.58, p=0.01) and 250Hz(Aδ-fiber, r=0.6, p=0.01)] but not unmyelinated sensory fiber current thresholds. These findings suggest that in SCD mice, rapamycin increases HbF and modulates current thresholds of myelinated fibers. Therefore, mTOR signaling might be implicated in the pathobiology of SCD.
胎儿血红蛋白诱导疗法可改善疾病状况并减轻镰状细胞病（SCD）的疼痛表型。雷帕霉素是一种哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，在体外可增加红系前体细胞中的胎儿血红蛋白（HbF）水平。我们推测雷帕霉素会提高SCD小鼠的HbF水平并改善伤害感受表型。我们使用正弦波电刺激来检查伤害防御表型，并评估有髓[2000Hz（Aβ纤维）和250Hz（Aδ纤维）]和无髓（5Hz C纤维）感觉纤维功能。雷帕霉素显著提高了γ-珠蛋白mRNA和HbF水平[增加2.3%（0.7，3.9），平均增加幅度（95%置信区间，CI），p=0.006]。在纯合（镰状化）小鼠中，长期（16周）而非短期（6周）的雷帕霉素治疗可提高2000Hz和250Hz的电流阈值，且该模式因性别而异。在雄性而非雌性小鼠中，雷帕霉素（与赋形剂相比）与2000Hz[21单位（7，35），平均差异（95%CI），性别*治疗交互作用p=0.009]和250Hz[9单位（1，16），p=0.01]电流阈值的增加有关。在接受雷帕霉素治疗的纯合子中，HbF水平与有髓[2000Hz（Aβ纤维，r=0.58，p=0.01）和250Hz（Aδ纤维，r=0.6，p=0.01）]而非无髓感觉纤维电流阈值直接相关。这些发现表明，在SCD小鼠中，雷帕霉素可增加HbF并调节有髓纤维的电流阈值。因此，mTOR信号传导可能与SCD的病理生物学有关。
