Department of Environmental Health, Program in Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Toxicol Sci. 2010 Jul;116(1):113-21. doi: 10.1093/toxsci/kfq104. Epub 2010 Apr 12.
We investigated differences in the pulmonary and systemic clearance of Stachybotrys chartarum spores in two strains of mice, BALB/c and C57BL/6J. To evaluate clearance, mice were intratracheally instilled with a suspension of radiolabeled S. chartarum spores or with unlabeled spores. The lungs of C57BL/6J mice showed more rapid spore clearance than the lungs of BALB/c mice, which correlated with increased levels of spore-associated radioactivity in the GI tracts of C57BL/6J as compared with BALB/c mice. To identify mechanisms responsible for mouse strain differences in spore clearance and previously described lung inflammatory responses, we exposed alveolar macrophages (AMs) lavaged from BALB/c and C57BL/6J mice to S. chartarum spores, S. chartarum spore toxin (SST), and satratoxin G (SG) in vitro. The S. chartarum spores were found to be highly toxic with most cells from either mouse strain being killed within 24 h when exposed to a spore:cell ratio of 1:75. The spores were more lethal to AMs from C57BL/6J than those from BALB/c mice. In mice, the SST elicited many of the same inflammatory responses as the spores in vivo, including AM recruitment, pulmonary hemorrhage, and cytokine production. Our data suggest that differences in pulmonary spore clearance may contribute to the differences in pulmonary responses to S. chartarum between BALB/c and C57BL/6J mice. Enhanced AM survival and subsequent macrophage-mediated inflammation may also contribute to the higher susceptibility of BALB/c mice to S. chartarum pulmonary effects. Analogous genetic differences among humans may contribute to reported variable sensitivity to S. chartarum.
我们研究了两种小鼠品系（BALB/c 和 C57BL/6J）中，杂色曲霉菌孢子在肺部和全身的清除差异。为了评估清除率，我们通过气管内滴注放射性标记的杂色曲霉菌孢子悬浮液或未标记的孢子来进行实验。与 BALB/c 小鼠相比，C57BL/6J 小鼠的肺部清除孢子的速度更快，这与 C57BL/6J 小鼠的胃肠道中与孢子相关的放射性水平升高有关。为了确定导致小鼠品系在孢子清除和先前描述的肺部炎症反应方面差异的机制，我们将从 BALB/c 和 C57BL/6J 小鼠中冲洗出的肺泡巨噬细胞（AMs）暴露于杂色曲霉菌孢子、杂色曲霉菌孢子毒素（SST）和 satratoxin G（SG）中，进行体外实验。结果发现，杂色曲霉菌孢子具有很高的毒性，当以 1:75 的孢子：细胞比例暴露于两种小鼠品系的大多数细胞时，在 24 小时内大多数细胞都被杀死。与 BALB/c 小鼠的 AMs 相比，C57BL/6J 小鼠的 AMs 更容易被孢子杀死。在小鼠体内，SST 引发了许多与体内孢子相同的炎症反应，包括 AM 募集、肺出血和细胞因子产生。我们的数据表明，肺部孢子清除率的差异可能导致 BALB/c 和 C57BL/6J 小鼠对杂色曲霉菌的肺部反应存在差异。增强的 AM 存活和随后的巨噬细胞介导的炎症也可能导致 BALB/c 小鼠对杂色曲霉菌肺部效应的更高易感性。人类中类似的遗传差异可能导致报告的对杂色曲霉菌的敏感性存在差异。
