Lingampally Arun, Jones Matthew R, Bagari Shirisha, Chen Chengshui, Rivetti Stefano, Bellusci Saverio
Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Pulmonary and Critical Care Medicine and Infectious Diseases, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Cardio-Pulmonary Institute, Justus-Liebig University Giessen, Giessen, Germany.
Front Bioeng Biotechnol. 2020 Sep 15;8:569865. doi: 10.3389/fbioe.2020.569865. eCollection 2020.
Idiopathic Pulmonary Fibrosis (IPF) is an end-stage lung disease characterized by excessive extracellular matrix (ECM) deposition from activated myofibroblasts (MYFs) and tissue scarring. Eventually leading to stiffening of the lung, capable of assuming only limited gas exchange function. So far two drugs, pirfenidone [acting via TGF-β (transforming growth factor beta) inhibition] and nintedanib (a pan-tyrosine kinase receptor inhibitor) have been approved for IPF patients. They both act on the activated MYF by reducing the expression of fibrotic markers. Unfortunately, these drugs are only slowing down fibrosis formation and as such do not represent a cure for this lethal, devastating disease. We previously reported that activated MYF originate, at least in part, from lung fibroblast resident cells called lipofibroblasts (LIF). During resolution, these activated MYF can transdifferentiate into LIF. We propose that this reversible myogenic/lipogenic transdifferentiation switch paradigm can be used to screen for drugs capable of triggering the lipogenic differentiation of activated MYFs. Ideally, these drugs should also induce the reduction of pro-fibrotic markers alpha smooth muscle actin2 (ACTA2) and collagen 1A1 (COL1A1) in activated MYF and as such would represent important alternatives to the approved drugs. The goal of this review is to summarize the current knowledge and limitations of the current strategies aiming to carry out methodical pre-clinical drug screening in pertinent , , and models of IPF. These models include (1) culture of primary fibroblasts from IPF patients, (2) culture of precision cut lung slices from end-stage IPF lungs obtained from transplant patients, and (3) bleomycin-induced fibrosis mouse models in the context of lineage tracing of activated MYF during resolution. For all these assays, we propose the innovative use of lipogenic read outs for the LIFs.
特发性肺纤维化（IPF）是一种终末期肺部疾病，其特征是活化的肌成纤维细胞（MYFs）过度沉积细胞外基质（ECM）并导致组织瘢痕形成。最终导致肺部僵硬，仅能发挥有限的气体交换功能。到目前为止，已有两种药物，吡非尼酮[通过抑制转化生长因子β（TGF-β）起作用]和尼达尼布（一种泛酪氨酸激酶受体抑制剂）被批准用于IPF患者。它们都通过降低纤维化标志物的表达来作用于活化的MYF。不幸的是，这些药物只能减缓纤维化的形成，因此并不能治愈这种致命的、具有破坏性的疾病。我们之前报道过，活化的MYF至少部分起源于称为脂肪成纤维细胞（LIF）的肺成纤维细胞驻留细胞。在纤维化消退过程中，这些活化的MYF可以转分化为LIF。我们提出，这种可逆的肌源性/脂肪生成性转分化开关模式可用于筛选能够触发活化MYF脂肪生成性分化的药物。理想情况下，这些药物还应诱导活化的MYF中促纤维化标志物α平滑肌肌动蛋白2（ACTA2）和胶原蛋白1A1（COL1A1）的减少，因此将成为已批准药物的重要替代物。本综述的目的是总结当前在IPF相关的、、和模型中进行系统的临床前药物筛选的策略的现有知识和局限性。这些模型包括：（1）IPF患者原代成纤维细胞培养；（2）从移植患者获得的终末期IPF肺的精密肺切片培养；（3）在纤维化消退过程中对活化的MYF进行谱系追踪的博来霉素诱导的肺纤维化小鼠模型。对于所有这些检测，我们建议对LIF采用创新的脂肪生成性读数方法。
