Department of Microbiology & Immunology, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, United States.
Exp Gerontol. 2012 Dec;47(12):958-65. doi: 10.1016/j.exger.2012.08.013. Epub 2012 Sep 7.
Rapamycin, a potent immunomodulatory drug, has shown promise in the amelioration of numerous age-associated diseases including cancer, Alzheimer's disease and cardiac hypertrophy. Yet the elderly, the population most likely to receive therapeutic rapamycin, are already at increased risk for infectious disease; thus concern exists that rapamycin may exacerbate age-associated immune dysfunctions and worsen infection outcomes. Herein, we examined the impact of enteric delivered rapamycin monotherapy (eRapa) on the susceptibility of aged (22-24month) C57BL/6 mice to Streptococcus pneumoniae, the leading bacterial cause of community-acquired pneumonia. Following challenge with S. pneumoniae, administration of eRapa conferred modest protection against mortality. Reduced mortality was the result of diminished lung damage rather than reduced bacterial burden. eRapa had no effect on basal levels of Interleukin (IL)-1α, IL-6, IL-10, IL-12p70, KC, Interferon-γ, Tumor necrosis factor α and Monocyte chemotactic protein-1 in whole lung homogenates or during pneumococcal pneumonia. Previously we have demonstrated that cellular senescence enhances permissiveness for bacterial pneumonia through increased expression of the bacterial ligands Laminin receptor (LR), Platelet-activating factor receptor (PAFr) and Cytokeratin 10 (K10). These proteins are co-opted by S. pneumoniae and other respiratory tract pathogens for host cell attachment during lung infection. UM-HET3 mice on eRapa had reduced lung cellular senescence as determined by levels of the senescence markers p21 and pRB, but not mH2A.1. Mice on eRapa also had marked reductions in PAFr, LR, and K10. We conclude that eRapa protected aged mice against pneumonia through reduced lung cellular senescence, which in turn, lowered bacterial ligand expression.
雷帕霉素是一种有效的免疫调节药物，在改善多种与年龄相关的疾病方面显示出了潜力，包括癌症、阿尔茨海默病和心脏肥大。然而，老年人是最有可能接受雷帕霉素治疗的人群，他们已经面临着传染病的风险增加；因此，人们担心雷帕霉素可能会加重与年龄相关的免疫功能障碍，并恶化感染的结果。在此，我们研究了肠内给予雷帕霉素单药治疗（eRapa）对 22-24 月龄 C57BL/6 老年小鼠对肺炎链球菌易感性的影响，肺炎链球菌是社区获得性肺炎的主要细菌性病因。在接受肺炎链球菌挑战后，给予 eRapa 可适度降低死亡率。死亡率降低是由于肺部损伤减少而不是细菌负荷减少所致。eRapa 对整个肺匀浆中基础水平的白细胞介素（IL）-1α、IL-6、IL-10、IL-12p70、KC、干扰素-γ、肿瘤坏死因子-α和单核细胞趋化蛋白-1没有影响，也没有影响肺炎链球菌肺炎期间的这些水平。之前我们已经证明，细胞衰老通过增加细菌配体层粘连蛋白受体（LR）、血小板激活因子受体（PAFr）和角蛋白 10（K10）的表达，增强了对细菌性肺炎的易感性。这些蛋白被肺炎链球菌和其他呼吸道病原体在肺部感染期间被宿主细胞用来附着。eRapa 治疗的 UM-HET3 小鼠的肺部细胞衰老程度降低，这可以通过衰老标志物 p21 和 pRB 的水平来确定，但不是 mH2A.1。用 eRapa 治疗的小鼠的 PAFr、LR 和 K10 也明显减少。我们的结论是，eRapa 通过降低肺部细胞衰老来保护老年小鼠免受肺炎的侵害，这反过来又降低了细菌配体的表达。
