Pulmonary fibrosis is a hallmark pathology seen across many interstitial lung diseases (ILDs) including idiopathic pulmonary fibrosis (IPF), scleroderma, sarcoidosis, and severe asthma. The drivers behind initiation and progression of pulmonary fibrosis are unclear and chemically induced preclinical models, such as bleomycin-induced lung fibrosis, have poor predictive value for drugs going towards the clinic. In contrast, Fos-related antigen 2 overexpressing transgenic mice (Fra2-Tg), develop a spontaneous, age-dependent progressive lung fibrosis and allowed us to evaluate the signatures of inflammation and fibrosis at three stages corresponding to pre-onset, inflammatory-dominant, and fibrosis-dominant biology.
Transcriptomic analysis of lungs revealed early increases in cytokine-cytokine receptor interactions and antigen processing and presentation pathways followed by enhanced Th2 and M2-macrophage driven type 2 responses. This type2 Inflammation progressed to extensive fibrotic signatures by 14-16 weeks of age. Further immune profiling showed highly enhanced GATA3+ Th2 cells and mannose-receptor (Mrc1) positive M2-macrophages. Treatment of Fra2-Tg mice with a bispecific antibody targeting IL-4 and IL-13 during the intermediate phase of the disease abrogated the Th2 and M2-responses; however the ECM deposition was only marginally impacted. Analysis of lungs and PBMCs from IPF patients revealed a similar increase in Th2 and M2-related genes and the abundance of CD206+ M2-Macrophages correlated with disease progression.
These data suggest that Fra-Tg mice recapitulate important features of pulmonary fibrosis and may be an valuable tool for both understanding the pathobiology of IPF and for testing therapeutic-agents targeting pulmonary fibrosis.