Abstract
Idiopathic Pulmonary Fibrosis (IPF) is the most severe form of chronic Interstitial Lung Disease, and characterized by progressive respiratory failure leading to a fatal issue. IPF natural history is heterogeneous, and its evolution is unpredictable. While most patients present a progressive decline of respiratory function over years, some patients remain stable but others present a fast deterioration of pulmonary function and respiratory failure without any identifiable cause. This sudden and rapid respiratory distress has been qualified of acute exacerbation (AE). The goal of the present study was to develop and characterize at the functional, histopathological, cellular and molecular levels a new mouse model of AE in pulmonary fibrosis mimicking IPF-AE. We first established a chronic pulmonary fibrosis using the repetitive low-dose BLM regimen (4 bi-weekly IT instillations of BLM), and then surimposed a double-dose BLM challenge to induce AE. As compared with classical low-dose repetitive BLM regimens, this AE model induced late animal mortality, worsened lung fibrosis and remodeling, and induced superadded histopathological features observed in IPF-AE in humans. Indeed, it was associated with stronger inflammation with increased macrophage infiltration of lung tissues and increased levels of pro-inflammatory cytokines in lung homogenates. Finally, expression of HIF1, the hallmark of tissular hypoxia and a major player in IPF progression is observed. This new model is a promising model of AE in chronic pulmonary fibrosis that could be useful to mimic IPF-AE.
Published Version
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