Comparative study on mouse models of acute exacerbation of pulmonary fibrosis

Le résumé fourni par la source

The etiology and underlying mechanisms of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) remain poorly understood. Although several animal models have been developed to study AE-IPF, a systematic evaluation and comparison of these models has not yet been reported. In the present study, PF was induced in mice by a single intratracheal administration of bleomycin (BLM). On day 14 after the initial BLM challenge, AE-PF in mice was induced by intratracheal re-challenge with replication-deficient adenoviral vectors (ADV), lipopolysaccharide (LPS) or a second dose of BLM. Micro-chest computed tomography (CT) was performed on day 20, and blood, bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected after sacrifice on day 21. Compared with mice receiving a single dose of BLM alone, all three AE-PF groups exhibited significant body weight loss and increased mortality (with the highest mortality in the LPS group), as well as more extensive lung injury on CT. Histopathological scores for inflammation and fibrosis, hydroxyproline content and expression levels of fibrotic markers (fibronectin, collagen I, α-smooth muscle actin and MMP7) were significantly elevated in the AE-PF groups. Inflammatory cytokines (IL-6, IL-1β and TNF-α) were markedly increased in both serum and BALF. Furthermore, the AE-PF models showed downregulation of alveolar epithelial cell markers (E-cadherin and pro-surfactant protein C) and a significant increase in apoptotic activity. Notably, fibrosis progression was more severe in the ADV and two-dose BLM groups than in the LPS group. Taken together, these findings indicate that all three triggers can induce AE-PF through enhanced apoptosis, inflammation and fibrosis. These results support the use of day 14 re-challenge as a standardized model for AE-PF. Among the three models, the ADV-induced AE-PF model may serve as a particularly suitable platform for investigating the pathogenesis of acute exacerbations in idiopathic pulmonary fibrosis.

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