Bimodal fibrosis in a novel mouse model of bleomycin-induced usual interstitial pneumonia

ABSTRACT Idiopathic pulmonary fibrosis (IPF) is pathologically classified 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 i nduced-UIP (iUIP) model, inducing fibrosis in D1CC×D1BC transgenic mice by intra-tracheal instillation of b leomycin mixed with m icrobubbles followed by s onoporation (BMS). A bimodal fibrotic lung disease was observed over 14 weeks, 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 Scgb1a1 and/or keratin 5 positive. This iUIP mouse model displays key features of IPF 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. Summary blurb A novel mouse model of induced-usual interstitial pneumonia shows bimodal fibrosis with honeycombing, similar to chronic lung disease seen with idiopathic pulmonary fibrosis.