Lung response to crystalline silica exposure in rats

Exposure to crystalline silica results in serious health effects, most notably, silicosis and cancer. An understanding of the silica-induced lung toxicity is critical for the intervention and/or prevention of its adverse health effects. Rats were exposed by inhalation to air or crystalline silica (15 mg/m3, 6 hours/day for 5 days). At post-exposure time intervals of 1, 3, 6, 9, 12, and 18 months, the control and silica exposed rats were euthanized, and lung toxicity and gene expression profiles determined. Histological changes indicative of lung toxicity detected in the silica exposed rats included infiltration of neutrophils, thickening of alveolar epithelium, and fibrosis. Significant increases in lactate dehydrogenase activity, number of phagocytes, and inflammatory cytokine levels were detected in the bronchoalveolar lavage (BAL) obtained from the silica exposed rats compared with the corresponding time-matched controls. Significant changes in lung gene expression profiles, corresponding to the changes in the lung toxicity parameters analyzed, were detected in the silica exposed rats. The BAL parameters of toxicity and inflammation peaked at the 12-months post-exposure time interval and declined subsequently. However, lung fibrosis continued to progress being highest at the 18-month post-exposure time interval. These results suggest that inflammation may be required for the initiation but not for the progression and/or maintenance of lung fibrosis in response to silica exposure in the rats.暴露于结晶型二氧化硅会引发严重健康损害，其中尤以矽肺与癌症最为显著。阐明二氧化硅诱导的肺毒性机制，对于干预乃至预防其所致的健康危害至关重要。本研究通过吸入方式让大鼠分别暴露于空气或结晶型二氧化硅（浓度15 mg/m³，每日6小时，连续5天）。分别于暴露后1、3、6、9、12及18个月时，对对照组与二氧化硅暴露组大鼠实施安乐死，并检测其肺毒性指标与基因表达谱。二氧化硅暴露组大鼠中检测到的提示肺毒性的组织学改变包括中性粒细胞浸润、肺泡上皮增厚以及肺纤维化。与同期配对对照组相比，二氧化硅暴露组大鼠的支气管肺泡灌洗液（bronchoalveolar lavage, BAL）中，乳酸脱氢酶活性、吞噬细胞数量及炎症细胞因子水平均显著升高。二氧化硅暴露组大鼠的肺组织基因表达谱亦出现显著改变，且与所检测的肺毒性参数变化相一致。支气管肺泡灌洗液的毒性与炎症参数于暴露后12个月达到峰值，随后逐渐下降。但肺纤维化仍持续进展，并于暴露后18个月达到最高水平。本研究结果表明，在大鼠二氧化硅暴露诱导的肺损伤中，炎症反应可能是肺纤维化启动的必要条件，但并非纤维化进展与维持的必需因素。