| Research Abstract |
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
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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
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