权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Effects of diesel exhaust particles on diabetes mellitus and its complications

柴油机尾气颗粒物对糖尿病及其并发症的影响

基本信息

批准号：
15310030
负责人：
TAKANO Hirohisa
金额：
$ 4.8万
依托单位：
National Institute for Environmental Studies
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Epidemiology studies demonstrate serious adverse effects of particulate air pollution on the predisposed people that have cardiovascular diseases, respiratory diseases, and diabetes mellitus. However, the underlying molecular mechanism remains to be elucidated. To provide experimental evidence for the epidemiological data, we first determined the effects of diesel exhaust particles (DEP), major participants in particulate pollutants, on lung injury related to bacterial infection in mice. Intratracheal instillation of DEP dramatically enhanced lung injury related to endotoxin from gram-negative bacteria, which was characterized by neutrophil sequestration, interstitial edema, and alveolar hemorrhage. In the presence of endotoxin, DEP markedly activated the nuclear translocation of p65 subunit of nuclear factor kappa B (NF kappa B) in the lung, and increased the lung expression of Toll-like receptors, intercellular adhesion molecule-1, interleukin (IL)-1 beta, IL-8, macrophage chemoattra … More ctant protein-1 (MCP-1), and macrophage inflammatory protein-1 alpha (MIP-1 alpha) in particular. DEP given alone increased the lung expression of Toll-like receptor 4 and nuclear localization of p50 subunit of NF kappa B. These results provide the first experimental evidence that DEP enhance lung injury related to bacterial infection and comparable to acute respiratory distress syndrome in human. The enhancement is mediated likely through the expression of Toll-like receptors, the activation of p65-containing dimer(s) of NF kappa B such as p65/p50, and the subsequent induction of proinflammatory molecules in particular MIP-1 alpha.Next, we examined the effects of the organic chemicals including polycyclic aromatic hydrocarbons (DEP-PAH) and the residual carbonaceous nuclei (washed DEP) derived from DEP on the endoxin-related lung injury. DEP-PAH or washed DEP enhanced the infiltration of neutrophils in bronchoalveolar lavage fluid in the presence of bacterial endotoxin. Washed DEP combined with endotoxin synergistically exacerbated pulmonary edema and induced alveolar hemorrhage, which was concomitant with the enhanced lung expression of IL-1β, MIP-1a, MCP-1, and IL-8, whereas DEP-PAH combined with LPS did not. The gene expression for Toll-like receptor 2 and 4 was increased by the combined treatment with washed DEP and bacterial endotoxin. These results suggest that the residual carbonaceous nuclei of DEP predominantly contribute to the aggravation of endotoxin-related lung injury rather than the extracted organic chemicals from DEP. The aggravation may be mediated through the expression of proinflammatory cytokines, chemokines, and Toll-like receptors.Thirdly, we determined whether DEP or DEP components can modify the coagulatory and fibrinolytic disturbances. Intratracheal exposure to bacterial endotoxin increased the circulatory levels of fibrinogen and its degradable products, which was significantly enhanced by washed DEP coexposure. The results suggest that exposure to DEP can affect thrombohemostatic disorders especially in the setting og respiratori infection.Finally, we determined the effects of intratracheal exposure to DEP on diabetic organ complications. DEP apparently exaggerated fatty liver related to diabetes mellitus in mice. Less

流行病学研究表明，空气颗粒物污染对心血管疾病、呼吸系统疾病和糖尿病易感人群有严重的不良影响。然而，潜在的分子机制仍有待阐明。为了给流行病学数据提供实验依据，我们首先确定了颗粒污染物的主要参与者柴油机排气颗粒（DEP）对小鼠细菌感染相关肺损伤的影响。气管内滴注DEP可显著增强革兰氏阴性菌内毒素引起的肺损伤，其特征为中性粒细胞隔离、间质水肿和肺泡出血。内毒素作用下，DEP可显著激活肺组织核因子κ B（NF κ B B）p65亚单位核转位，增加肺组织Toll样受体、细胞间粘附分子1、白细胞介素（IL）1 β、IL-8、巨噬细胞趋化因子（巨噬细胞趋化因子）、巨噬细胞因子（巨噬细胞因子）、巨 ...更多信息巨噬细胞炎性蛋白-1（MCP-1），特别是巨噬细胞炎性蛋白-1 α（MIP-1 α）。DEP单独给药可增加肺Toll样受体4的表达和NF κ B B p50亚单位的核定位。这些结果提供了第一个实验证据，DEP增强与细菌感染有关的肺损伤，并与急性呼吸窘迫综合征在人类。这种增强可能通过Toll样受体的表达、NF κ B B的含p65的二聚体（例如p65/p50）的活化以及随后的促炎分子（特别是MIP-1 α）的诱导来介导。研究了多环芳烃（DEP-PAH）和残余碳核等有机物对碳纳米管的影响（洗涤的DEP）对内毒素相关的肺损伤的作用。在细菌内毒素存在下，DEP-PAH或洗涤DEP增强支气管肺泡灌洗液中中性粒细胞的浸润。DEP与内毒素联合应用可协同加重肺水肿和诱导肺泡出血，并伴有肺组织IL-1β、MIP-1a、MCP-1和IL-8的表达增强，而DEP-PAH与LPS联合应用则无此作用。Toll样受体2和4的基因表达增加洗涤DEP和细菌内毒素的组合处理。这些结果表明，残留的碳核DEP主要有助于加重内毒素相关的肺损伤，而不是从DEP提取的有机化学品。这种加重可能是通过促炎细胞因子、趋化因子和Toll样受体的表达介导的。第三，我们确定了DEP或DEP组分是否可以改变凝血和纤溶障碍。细菌内毒素暴露增加了血液中纤维蛋白原及其降解产物的水平，这是显着增强洗涤DEP共同曝光。结果表明，暴露于DEP可以影响血栓止血障碍，特别是在设置的胃肠道感染。最后，我们确定的影响，颅内暴露于DEP糖尿病器官并发症。DEP明显加重小鼠糖尿病相关脂肪肝。少