Effects of diesel exhaust particles on diabetes mellitus and its complications

流行病学研究表明，颗粒物空气污染对患有心血管疾病、呼吸系统疾病和糖尿病的易感人群产生严重的不利影响。然而，其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证据，我们首先确定了颗粒物污染物的主要参与者柴油废气颗粒物(DEP)对与细菌感染相关的小鼠肺损伤的影响。气管内滴注DEP可显著加重由革兰氏阴性菌内毒素引起的以中性粒细胞隔离、间质水肿和肺泡出血为特征的肺损伤。在内毒素存在的情况下，DEP可显著激活肺组织核因子kappaB p65亚单位的核转位，增加肺组织Toll样受体、细胞间黏附分子-1、白介素1β、白介素8、巨噬细胞趋化因子…的表达更多的是Cant蛋白-1(MCP-1)，尤其是巨噬细胞炎性蛋白-1α(MIP-1α)。单独给予DEP可增加肺组织Toll样受体4的表达和核转录因子kappaB p50亚单位的核定位。这些结果首次提供了DEP增强与细菌感染相关的肺损伤的实验证据，可与人类急性呼吸窘迫综合征相媲美。这种增强可能是通过表达Toll样受体，激活含有p65的核因子kappa B的二聚体(S)，如p65/p50，以及随后诱导的促炎分子，特别是MIP-1α。接下来，我们研究了包括多环芳烃(DEP-PAH)在内的有机化合物(DEP-PAH)和来自DEP的残留碳核(洗涤的DEP)对内毒素相关性肺损伤的影响。在细菌内毒素存在的情况下，DEP-PAH或洗涤的DEP可促进中性粒细胞在支气管肺泡灌洗液中的渗透。DEP联合内毒素可协同加重肺水肿和肺泡出血，并伴有肺组织IL-1β、MIP-1a、MCP-1和IL-8的表达增加，而DEP-PAH和内毒素联合应用则无明显作用。洗涤DEP和细菌内毒素联合作用后，Toll样受体2和Toll样受体4的基因表达增加。这些结果表明，DEP中残留的碳核是内毒素相关性肺损伤加重的主要原因，而不是DEP中提取的有机化合物。这种加重可能是通过促炎细胞因子、趋化因子和Toll样受体的表达来调节的。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。气管内暴露于细菌内毒素可增加循环中纤维蛋白原及其可降解产物的水平，洗涤DEP联合暴露可显著提高这一水平。结果表明，接触DEP可影响血栓止血障碍，尤其是在呼吸道感染的情况下。最后，我们确定了气管内接触DEP对糖尿病器官并发症的影响。DEP可明显加重糖尿病小鼠的脂肪肝。较少

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