Department of Neurodevelopmental Disorder Genetics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
Life Sci Alliance. 2021 Nov 2;5(1). doi: 10.26508/lsa.202101059. Print 2022 Jan.
Idiopathic pulmonary fibrosis is pathologically represented by usual interstitial pneumonia (UIP). Conventional bleomycin models used to study pathogenic mechanisms of pulmonary fibrosis display transient inflammation and fibrosis, so their relevance to UIP is limited. We developed a novel chronic induced-UIP (iUIP) model, inducing fibrosis in D1CC×D1BC transgenic mice by intra-tracheal instillation of bleomycin mixed with microbubbles followed by sonoporation (BMS). A bimodal fibrotic lung disease was observed over 14 wk, with an acute phase similar to nonspecific interstitial pneumonia (NSIP), followed by partial remission and a chronic fibrotic phase with honeycombing similar to UIP. In this secondary phase, we observed poor vascularization despite elevated PDGFRβ expression. γ2PF- and MMP7-positive epithelial cells, consistent with an invasive phenotype, were predominantly adjacent to fibrotic areas. Most invasive cells were and/or positive. This iUIP mouse model displays key features of idiopathic pulmonary fibrosis and has identified potential mechanisms contributing to the onset of NSIP and progression to UIP. The model will provide a useful tool for the assessment of therapeutic interventions to oppose acute and chronic fibrosis.
特发性肺纤维化在病理学上表现为寻常型间质性肺炎（UIP）。用于研究肺纤维化发病机制的常规博来霉素模型显示出短暂的炎症和纤维化，因此与 UIP 的相关性有限。我们开发了一种新型的慢性诱导 UIP（iUIP）模型，通过气管内滴注博来霉素和微泡混合物，然后进行声穿孔（BMS），在 D1CC×D1BC 转基因小鼠中诱导纤维化。在 14 周的时间里观察到双相纤维性肺病，急性相类似于非特异性间质性肺炎（NSIP），随后部分缓解和慢性纤维化期出现类似于 UIP 的蜂窝状改变。在这个次要阶段，尽管 PDGFRβ表达升高，但观察到血管生成不良。与侵袭表型一致的 γ2PF-和 MMP7 阳性上皮细胞主要位于纤维化区域附近。大多数侵袭性细胞为 和/或 阳性。这种 iUIP 小鼠模型显示了特发性肺纤维化的关键特征，并确定了导致 NSIP 发作和进展为 UIP 的潜在机制。该模型将为评估对抗急性和慢性纤维化的治疗干预措施提供有用的工具。
