Daly H E, Baecher-Allan C M, Barth R K, D'Angio C T, Finkelstein J N
Department of Environmental Medicine, University of Rochester, New York 14642, USA.
Toxicol Appl Pharmacol. 1997 Feb;142(2):303-10. doi: 10.1006/taap.1996.8056.
Clinical use of the antineoplastic agent bleomycin is restricted due to pulmonary toxicity. Murine models of bleomycin-induced pulmonary fibrosis have been developed in an attempt to understand the mechanisms involved in the fibrotic process. Studies have shown that the alveolar epithelium is damaged early after bleomycin treatment. The purpose of this study was to evaluate the pattern of gene expression in airway and alveolar epithelial cells after bleomycin exposure in mice that vary in susceptibility to bleomycin-induced fibrosis. Surfactant protein C (SPC) and Clara cell-specific protein (CC10) mRNA were used as cell-specific markers of alveolar type II cells and airway Clara cells, respectively. Mice were treated with a single intratracheal dose of bleomycin and the pattern of SPC and CC10 transcripts was examined by in situ hybridization. The pattern of SPC mRNA 28 days after treatment was uniform in controls and resistant mice but exhibited a patchy appearance in sensitive mice. Bleomycin treatment also resulted in a strain-dependent loss of CC10 mRNA-expressing cells. In sensitive mice 28 days after treatment, SPC mRNA was ectopically expressed in the distal bronchiolar epithelium in a morphologically distinct cell type. Serial sections revealed that these cells either coexpressed CC10 mRNA or were located adjacent to CC10 mRNA-containing cells. This unique cell population may represent a progenitor cell type important in epithelial repair. The strain-dependent changes in CC10 and SPC gene expression after bleomycin treatment are suggestive of a role for the epithelium in pulmonary fibrosis versus repair.
由于存在肺毒性，抗肿瘤药物博来霉素的临床应用受到限制。为了了解纤维化过程中涉及的机制，人们建立了博来霉素诱导的小鼠肺纤维化模型。研究表明，博来霉素治疗后早期肺泡上皮就会受损。本研究的目的是评估博来霉素诱导纤维化易感性不同的小鼠在暴露于博来霉素后气道和肺泡上皮细胞中的基因表达模式。表面活性蛋白C（SPC）和克拉拉细胞特异性蛋白（CC10）mRNA分别用作II型肺泡细胞和气道克拉拉细胞的细胞特异性标志物。给小鼠气管内单次注射博来霉素，通过原位杂交检测SPC和CC10转录本的模式。治疗28天后，对照组和抗性小鼠中SPC mRNA的模式是均匀的，但在敏感小鼠中呈现出斑片状外观。博来霉素治疗还导致表达CC10 mRNA的细胞出现品系依赖性减少。在治疗28天后的敏感小鼠中，SPC mRNA在远端细支气管上皮中以形态学上不同的细胞类型异位表达。连续切片显示，这些细胞要么共表达CC10 mRNA，要么位于含有CC10 mRNA的细胞附近。这种独特的细胞群体可能代表上皮修复中重要的祖细胞类型。博来霉素治疗后CC10和SPC基因表达的品系依赖性变化提示上皮在肺纤维化与修复中起作用。
