Translation value of the bleomycin rat model for the treatment of patients with Idiopathic Pulmonary Fibrosis (IPF)

Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/¿-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/¿-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care.已知经气管内给予博莱霉素（bleomycin）可在短时间内诱导肺部发生炎症与纤维化反应，其组织病理学特征包括炎性细胞浸润、胶原沉积以及肺泡腔闭塞。由于特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）患者的肺部病变存在部分此类特征，博莱霉素诱导的肺纤维化动物模型因此被广泛应用。然而，在该动物模型中验证有效并推进至临床试验的探索性治疗方案，在人体试验中并未展现出显著疗效。本研究针对博莱霉素诱导的大鼠肺纤维化模型展开分析，采集了不同时间点的全基因组表达数据，并通过与特发性肺纤维化患者肺活检组织的全基因组表达数据进行比对，评估该模型与人类疾病的相关性。经比对发现，在博莱霉素滴注后7天的大鼠模型与人类IPF组织间，基因表达相关性达到最高水平。基于上述基因表达特征，本研究鉴定出12个与疾病相关的新型转化基因标志物，该标志物集可有效区分特发性肺纤维化患者与健康对照个体。此外，属于该转化基因标志物集的3个Wnt/β-连环蛋白（Wnt/β-catenin）通路相关基因，结合临床肺一氧化碳弥散量（diffusing capacity of the lung for carbon monoxide, DLCO）检测指标，可用于根据疾病严重程度对特发性肺纤维化患者进行分层。吡非尼酮可在博莱霉素诱导的纤维化模型中抑制部分转化基因标志物的表达，其中尤以与Wnt/β-连环蛋白信号通路相关的标志物为著。该新型转化基因标志物组不仅为在博莱霉素诱导的大鼠肺纤维化模型中评估新型治疗策略的疾病修饰疗效提供了更优手段，还可作为特发性肺纤维化患者诊疗的诊断与预后工具。