Della Latta Veronica, Cecchettini A, Del Ry S, Morales M A
CNR Clinical Physiology Institute, Pisa, Italy; University of Siena, Siena, Italy.
CNR Clinical Physiology Institute, Pisa, Italy; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Pharmacol Res. 2015 Jul;97:122-30. doi: 10.1016/j.phrs.2015.04.012. Epub 2015 May 8.
Bleomycin (BLM) is a drug used to treat different types of neoplasms. BLM's most severe adverse effect is lung toxicity, which induces remodeling of lung architecture and loss of pulmonary function, rapidly leading to death. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing lung fibrosis in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, epithelial cell injury with reactive hyperplasia, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced lung fibrosis in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced lung fibrosis and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
博来霉素（BLM）是一种用于治疗不同类型肿瘤的药物。BLM最严重的不良反应是肺毒性，它会导致肺结构重塑和肺功能丧失，迅速导致死亡。虽然其作为抗癌药物的临床作用有限，但由于BLM是诱导动物肺纤维化最常用的药物之一，在实验环境中的应用广泛，因为它能够引发与化疗患者相似的组织学肺模式。这种模式的特征是散在性实质炎症、上皮细胞损伤伴反应性增生、上皮-间质转化、成纤维细胞激活并分化为肌成纤维细胞、基底膜和肺泡上皮损伤。多项研究表明，BLM损伤是由DNA链断裂介导的，产生单链或双链断裂，导致自由基生成增加。到目前为止，肺纤维化发生发展所涉及的机制尚未完全明确；多项研究分析了各种潜在的生物分子因素，如转化生长因子β1、肿瘤坏死因子α、细胞外基质成分、伴侣蛋白、白细胞介素和趋化因子。本文旨在综述不同动物模型中BLM诱导的肺纤维化的具体特征，并总结体内给药的方式和时机。了解BLM诱导肺纤维化的机制以及常用的抗纤维化治疗方法，为将潜在的分子靶点从动物模型转化到临床领域提供了契机。
