Laboratoire Hypoxie & Poumon, UMR INSERM U1272, Université Sorbonne Paris-Nord, 93000 Bobigny, France.
Faculté de Médecine, Sorbonne Université, 75006 Paris, France.
Cells. 2022 Oct 26;11(21):3379. doi: 10.3390/cells11213379.
idiopathic pulmonary fibrosis (IPF) is the most severe form of fibrosing interstitial lung disease, characterized by progressive respiratory failure leading to death. IPF's natural history is heterogeneous, and its progression unpredictable. Most patients develop a progressive decline of respiratory function over years; some remain stable, but others present a fast-respiratory deterioration without identifiable cause, classified as acute exacerbation (AE).
to develop and characterize an experimental mice model of lung fibrosis AE, mimicking IPF-AE at the functional, histopathological, cellular and molecular levels.
we established in C57BL/6 male mice a chronic pulmonary fibrosis using a repetitive low-dose bleomycin (BLM) intratracheal (IT) instillation regimen (four instillations of BLM every 2 weeks), followed by two IT instillations of a simple or double-dose BLM challenge to induce AE. Clinical follow-up and histological and molecular analyses were done for fibrotic and inflammatory lung remodeling analysis.
as compared with a low-dose BLM regimen, this AE model induced a late burst of animal mortality, worsened lung fibrosis and remodeling, and superadded histopathological features as observed in humans IPF-AE. This was associated with stronger inflammation, increased macrophage infiltration of lung tissue and increased levels of pro-inflammatory cytokines in lung homogenates. Finally, it induced in the remodeled lung a diffuse expression of hypoxia-inducible factor 1α, a hallmark of tissular hypoxia response and a major player in the progression of IPF.
this new model is a promising model of AE in chronic pulmonary fibrosis that could be relevant to mimic IPF-AE in preclinical trials.
特发性肺纤维化（IPF）是最严重的肺纤维化间质性疾病，其特征是进行性呼吸衰竭导致死亡。IPF 的自然病史呈异质性，其进展不可预测。大多数患者在数年内出现呼吸功能进行性下降；有些患者保持稳定，但另一些患者则出现无明显原因的快速呼吸恶化，归类为急性加重（AE）。
开发和表征一种模拟 IPF-AE 在功能、组织病理学、细胞和分子水平的实验性肺纤维化 AE 小鼠模型。
我们使用重复低剂量博莱霉素（BLM）气管内（IT）滴注方案（每 2 周 BLM 滴注 4 次），在 C57BL/6 雄性小鼠中建立慢性肺纤维化，随后进行两次 IT 滴注简单或双倍剂量 BLM 挑战以诱导 AE。进行临床随访以及组织学和分子分析，以进行纤维化和炎症性肺重塑分析。
与低剂量 BLM 方案相比，该 AE 模型诱导动物死亡率晚发性爆发，加重肺纤维化和重塑，并叠加了人类 IPF-AE 中观察到的组织病理学特征。这与更强的炎症、肺组织中巨噬细胞浸润增加以及肺匀浆中促炎细胞因子水平升高有关。最后，它在重塑的肺中诱导缺氧诱导因子 1α的弥漫性表达，这是组织缺氧反应的标志，也是 IPF 进展的主要参与者。
这种新的模型是慢性肺纤维化 AE 的有前途的模型，可在临床前试验中模拟 IPF-AE。
