Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence.
Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence.
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DOI：
10.1016/j.exger.2012.08.013
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发表时间：
2012-12
影响因子：
3.9
通讯作者：
Orihuela, Carlos J.
中科院分区：
文献类型：
--
作者：
Hinojosa, Cecilia A.;Mgbemena, Victoria;Van Roekel, Sabrina;Austad, Steven N.;Miller, Richard A.;Bose, Santanu;Orihuela, Carlos J.
雷帕霉素是一种有效的免疫调节药物，在改善许多与年龄相关的疾病（包括癌症、阿尔茨海默氏病和心脏肥大）方面显示出良好的前景。然而，老年人是最有可能接受雷帕霉素治疗的人群，他们患传染病的风险已经增加；因此，人们担心雷帕霉素可能会加剧与年龄相关的免疫功能障碍并恶化感染结果。在此，我们研究了肠溶雷帕霉素单药疗法 (eRapa) 对老年（22-24 个月）C57BL/6 小鼠对肺炎链球菌（社区获得性肺炎的主要细菌原因）敏感性的影响。在受到肺炎链球菌攻击后，给予 eRapa 可提供一定程度的抗死亡保护。死亡率降低是肺损伤减少的结果，而不是细菌负担减少的结果。 eRapa 对全肺匀浆或肺炎球菌肺炎期间白介素 (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 的基础水平没有影响。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）和细胞角蛋白10（K10）的表达来增强细菌性肺炎的发生可能性。这些蛋白质在肺部感染期间被肺炎链球菌和其他呼吸道病原体选择用于宿主细胞附着。根据衰老标记物 p21 和 pRB 的水平确定，eRapa 上的 UM-HET3 小鼠肺细胞衰老减少，但 mH2A.1 没有。使用 eRapa 的小鼠的 PAFr、LR 和 K10 也显着降低。我们得出的结论是，eRapa 通过减少肺细胞衰老来保护老年小鼠免受肺炎的侵害，从而降低细菌配体的表达。
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 susceptibility of aged (22–24 month) 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.
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影响因子：
20.3
作者：
Hackstein, H;Taner, T;Thomson, AW
通讯作者：
Thomson, AW
影响因子：
11.8
作者：
Johansson, Niclas;Kalin, Mats;Hedlund, Jonas
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Hedlund, Jonas
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168.9
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Lopez, Alan D.;Mathers, Colin D.;Murray, Christopher J. L.
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Murray, Christopher J. L.
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Araki, Koichi;Turner, Alexandra P.;Shaffer, Virginia Oliva;Gangappa, Shivaprakash;Keller, Susanne A.;Bachmann, Martin F.;Larsen, Christian P.;Ahmed, Rafi
通讯作者：
Ahmed, Rafi
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4.3
作者：
Demidenko, Zoya N.;Zubova, Svetlana G.;Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.