Dubaybo B A, Durr R A, Thet L A
Department of Medicine, Duke University Medical Center, Durham, North Carolina.
J Toxicol Environ Health. 1987;22(4):439-57. doi: 10.1080/15287398709531084.
We describe a model of pulmonary fibrosis in which doses of paraquat ranging from 0.001 mg/kg to 1.0 mg/kg were instilled into the right lung of rats. Lung injury, as measured by right lung lavage albumin content and differential neutrophil count, ranged from undetectable to extremely severe, depending on the dose. Lung fibrosis, as assessed by collagen content and electron microscopy, showed similar dose-response effects. Mortality was minimal. Lavage fibronectin increased after high doses of paraquat, peaked at 2 d postinjury, decreased sharply after 3 d and was normal by 7 d. The temporal pattern was similar to that for albumin. Cultured alveolar macrophages obtained at 4 d postinjury did not have significant increases in fibronectin release. Tissue fibronectin content increased more slowly than lavage fibronectin, peaking at 4 d postinjury, and was still elevated at 7 and 14 d postinjury. Incorporation of [35S]methionine into tissue fibronectin by lung explants obtained at different times postinjury showed a similar time course. Lung collagen content increased steadily between 4 and 14 d postinjury. We conclude that, in our model, graded degrees of lung injury and fibrosis can be produced by varying the dose of unilaterally instilled paraquat and that the increases in lavage fibronectin were related mainly to capillary permeability whereas increases in tissue fibronectin represented parenchymal synthesis. The time course of changes in lung tissue fibronectin and collagen was consistent with the proposed roles of fibronectin in tissue repair and fibrosis. The ability of our model to produce graduated degrees of lung injury and fibrosis should be useful in further studies on the pathogenesis of postinjury lung fibrosis.
我们描述了一种肺纤维化模型，其中将剂量范围为0.001mg/kg至1.0mg/kg的百草枯注入大鼠右肺。根据右肺灌洗白蛋白含量和中性粒细胞分类计数来衡量，肺损伤程度从无法检测到极其严重不等，这取决于剂量。通过胶原蛋白含量和电子显微镜评估的肺纤维化显示出类似的剂量反应效应。死亡率极低。高剂量百草枯后灌洗纤维连接蛋白增加，在损伤后2天达到峰值，3天后急剧下降，7天时恢复正常。其时间模式与白蛋白相似。损伤后4天获得的培养肺泡巨噬细胞的纤维连接蛋白释放没有显著增加。组织纤维连接蛋白含量的增加比灌洗纤维连接蛋白慢，在损伤后4天达到峰值，在损伤后7天和14天仍升高。不同损伤时间获得的肺外植体将[35S]甲硫氨酸掺入组织纤维连接蛋白显示出类似的时间进程。肺胶原蛋白含量在损伤后4天至14天之间稳步增加。我们得出结论，在我们的模型中，通过改变单侧注入百草枯的剂量可以产生不同程度的肺损伤和纤维化，灌洗纤维连接蛋白的增加主要与毛细血管通透性有关，而组织纤维连接蛋白的增加代表实质合成。肺组织纤维连接蛋白和胶原蛋白变化的时间进程与纤维连接蛋白在组织修复和纤维化中的作用一致。我们的模型产生不同程度肺损伤和纤维化的能力应有助于进一步研究损伤后肺纤维化的发病机制。
