Porter Dale W, Millecchia Lyndell L, Willard Patsy, Robinson Victor A, Ramsey Dawn, McLaurin Jeffery, Khan Amir, Brumbaugh Kurt, Beighley Christoper M, Teass Alexander, Castranova Vincent
National Institute for Occupational Safety and Health, Health Effects Laboratory Division, Morgantown, WV 26505, USA.
Toxicol Sci. 2006 Mar;90(1):188-97. doi: 10.1093/toxsci/kfj075. Epub 2005 Dec 9.
Our laboratory has previously reported results from a rat silica inhalation study which determined that, even after silica exposure ended, pulmonary inflammation and damage progressed with subsequent fibrosis development. In the present study, the relationship between silica exposure, nitric oxide (NO) and reactive oxygen species (ROS) production, and the resultant pulmonary damage is investigated in this model. Rats were exposed to silica (15 mg/m3, 6 h/day) for either 20, 40, or 60 days. A portion of the rats from each exposure were sacrificed at 0 days postexposure, while another portion was maintained without further exposure for 36 days to examine recovery or progression. The major findings of this study are: (1) silica-exposed rat lungs were in a state of oxidative stress, the severity of which increased during the postexposure period, (2) silica-exposed rats had significant increase in lung NO production which increased in magnitude during the postexposure period, and (3) the presence of silica particle(s) in an alveolar macrophage (AM) was highly associated with inducible nitric oxide synthase (iNOS) protein. These data indicate that, even after silica exposure has ended, and despite declining silica lung burden, silica-induced pulmonary NO and ROS production increases, thus producing a more severe oxidative stress. A quantitative association between silica and expression of iNOS protein in AMs was also determined, which adds to our previous observation that iNOS and NO-mediated damage are associated anatomically with silica-induced pathological lesions. Future studies will be needed to determine whether the progressive oxidative stress, and iNOS activation and NO production, is a direct result of silica lung burden or a consequence of silica-induced biochemical mediators.
我们实验室之前报道了一项大鼠二氧化硅吸入研究的结果，该研究确定，即使二氧化硅暴露结束后，肺部炎症和损伤仍会随着随后的纤维化发展而进展。在本研究中，在该模型中研究了二氧化硅暴露、一氧化氮（NO）和活性氧（ROS）产生与由此导致的肺部损伤之间的关系。将大鼠暴露于二氧化硅（15 mg/m³，每天6小时）中20、40或60天。每次暴露的一部分大鼠在暴露后0天处死，而另一部分大鼠在无进一步暴露的情况下维持36天以检查恢复或进展情况。本研究的主要发现是：（1）暴露于二氧化硅的大鼠肺处于氧化应激状态，其严重程度在暴露后期间增加；（2）暴露于二氧化硅的大鼠肺中NO产生显著增加，在暴露后期间其幅度增大；（3）肺泡巨噬细胞（AM）中存在二氧化硅颗粒与诱导型一氧化氮合酶（iNOS）蛋白高度相关。这些数据表明，即使二氧化硅暴露已经结束，尽管二氧化硅肺负荷下降，但二氧化硅诱导的肺部NO和ROS产生增加，从而产生更严重的氧化应激。还确定了二氧化硅与AMs中iNOS蛋白表达之间的定量关联，这补充了我们之前的观察结果，即iNOS和NO介导的损伤在解剖学上与二氧化硅诱导的病理病变相关。未来需要进行研究以确定进行性氧化应激、iNOS激活和NO产生是二氧化硅肺负荷的直接结果还是二氧化硅诱导的生化介质的结果。
