Age-Associated Inflammation and Toll-Like Receptor Dysfunction Prime the Lungs for Pneumococcal Pneumonia
Age-Associated Inflammation and Toll-Like Receptor Dysfunction Prime the Lungs for Pneumococcal Pneumonia
复制标题
DOI：
10.1086/600870
复制
发表时间：
2009-08-15
影响因子：
6.4
通讯作者：
Orihuela, Carlos J.
中科院分区：
文献类型：
--
作者：
Hinojosa, Ernesto;Boyd, Angela R.;Orihuela, Carlos J.
背景衰老与炎症增加和社区获得性肺炎的风险有关。肺炎链球菌通过核因子κ B（NF κ B）调节蛋白多聚免疫球蛋白受体（pIgR）和血小板活化因子受体（PAFr）粘附和侵入细胞。我们试图确定衰老和慢性炎症是否与肺中pIgR和PAFr水平升高以及对S.肺炎感染。采用Western印迹和定量聚合酶链反应定量肺蛋白和信使RNA水平。通过电泳迁移率变动分析测量NF κ B活化。细胞因子水平通过细胞计数珠分析测量。为了建立慢性炎症模型，小鼠体内植入了渗透泵，输送肿瘤坏死因子-α。老年小鼠和注入肿瘤坏死因子-α的小鼠肺中pIgR和PAFr水平升高，对S.肺炎感染。在肺炎期间，老年小鼠的pIgR和PAFr水平降低，NFkB活化减少，尽管细菌负荷更大。我们确定老年小鼠肺Toll样受体1、2和4的数量减少，对S.肺炎与促炎细胞因子的产生。由于慢性炎症和Toll样受体功能障碍的引发效应，老年小鼠和老年人更容易患肺炎。
Background. Aging is associated with increased inflammation and risk of community-acquired pneumonia. Streptococcus pneumoniae co-opts the nuclear factor kappa B (NFkB)-regulated proteins polymeric immunoglobulin receptor (pIgR) and platelet-activating factor receptor (PAFr) to attach and invade cells. We sought to determine whether aging and chronic inflammation were associated with increased pIgR and PAFr levels in the lungs and increased susceptibility to S. pneumoniae infection.Methods. Lung protein and messenger RNA levels were quantitated using Western blot and quantitative polymerase chain reaction. NFkB activation was measured by electrophoretic mobility shift assay. Cytokine levels were measured by cytometric bead analysis. To model chronic inflammation, mice were implanted with osmotic pumps that delivered tumor necrosis factor-alpha.Results. Aged mice and those infused with tumor necrosis factor-alpha had increased levels of pIgR and PAFr in their lungs and were more susceptible to S. pneumoniae infection. During pneumonia, aged mice had reduced levels of pIgR and PAFr and less NFkB activation, despite greater bacterial burden. We determined that aged mice had decreased amounts of lung Toll-like receptors 1, 2, and 4 and reduced capacity to respond to S. pneumoniae with proinflammatory cytokine production.Conclusions. Aged mice and, potentially, elderly humans are more susceptible to pneumonia because of a priming effect of chronic inflammation and Toll-like receptor dysfunction.