Curriculum in Toxicology, University of North Carolina School of Medicine, Chapel Hill, NC 27711, USA.
Environ Health Perspect. 2012 Jan;120(1):85-91. doi: 10.1289/ehp.1103990. Epub 2011 Oct 6.
Surface-available iron (Fe) is proposed to contribute to asbestos-induced toxicity through the production of reactive oxygen species.
Our goal was to evaluate the hypothesis that rat models of cardiovascular disease with coexistent Fe overload would be increasingly sensitive to Libby amphibole (LA)-induced subchronic lung injury.
Male healthy Wistar Kyoto (WKY), spontaneously hypertensive (SH), and SH heart failure (SHHF) rats were intratracheally instilled with 0.0, 0.25, or 1.0 mg LA (with saline as the vehicle). We examined bronchoalveolar lavage fluid (BALF) and histological lung sections after 1 week, 1 month, or 3 months for pulmonary biomarkers and pathology. SHHF rats were also assessed at 6 months for pathological changes.
All animals developed concentration- and time-dependent interstitial fibrosis. Time-dependent Fe accumulation occurred in LA-laden macrophages in all strains but was exacerbated in SHHF rats. LA-exposed SHHF rats developed atypical hyperplastic lesions of bronchiolar epithelial cell origin at 3 and 6 months. Strain-related baseline differences existed in gene expression at 3 months, with persistent LA effects in WKY but not SH or SHHF rats. LA exposure altered genes for a number of pathways, including inflammation, immune regulation, and cell-cycle control. Cell-cycle control genes were inhibited after LA exposure in SH and SHHF but not WKY rats, whereas tumor suppressor genes were induced only in WKY rats. The inflammatory gene expression also was apparent only in WKY rats.
These data show that in Fe-overload conditions, progressive Fe accumulation occurs in fiber-laden macrophages within LA-induced lesions. Fe overload does not appear to contribute to chronic inflammation, and its role in hyperplastic lesion development requires further examination.
据提出，表面可用铁（Fe）通过产生活性氧物种而有助于石棉诱导的毒性。
我们的目标是评估以下假设，即患有共存铁过载的心血管疾病大鼠模型将对 Libby 角闪石（LA）诱导的亚慢性肺损伤变得更加敏感。
雄性健康的 Wistar Kyoto（WKY）、自发性高血压（SH）和 SH 心力衰竭（SHHF）大鼠通过气管内滴注 0.0、0.25 或 1.0mg LA（以生理盐水作为载体）。我们在 1 周、1 个月或 3 个月后检查了支气管肺泡灌洗液（BALF）和组织学肺切片，以评估肺生物标志物和病理学变化。还在 6 个月时评估了 SHHF 大鼠的病理变化。
所有动物均表现出浓度和时间依赖性的间质纤维化。在所有品系中，LA 负荷巨噬细胞中均出现时间依赖性的铁积累，但在 SHHF 大鼠中更为严重。在 3 个月和 6 个月时，暴露于 LA 的 SHHF 大鼠出现了源自细支气管上皮细胞的非典型增生性病变。在 3 个月时，存在与品系相关的基因表达基线差异，WKY 大鼠中存在持续的 LA 作用，但在 SH 或 SHHF 大鼠中则不存在。LA 暴露改变了许多通路的基因表达，包括炎症、免疫调节和细胞周期控制。在 SH 和 SHHF 大鼠中，LA 暴露后细胞周期控制基因受到抑制，但在 WKY 大鼠中则没有，而肿瘤抑制基因仅在 WKY 大鼠中诱导。炎症基因表达也仅在 WKY 大鼠中明显。
这些数据表明，在铁过载情况下，在 LA 诱导的病变内纤维负荷巨噬细胞中会发生渐进性铁积累。铁过载似乎不会导致慢性炎症，其在增生性病变发展中的作用需要进一步研究。
