Transcriptomic and Proteomic Changes Driving Pulmonary Fibrosis Resolution in Young and Old Mice.

Bleomycin-induced pulmonary fibrosis in mice mimics major hallmarks of idiopathic pulmonary fibrosis, yet in this model it spontaneously resolves over time. We studied molecular mechanisms of fibrosis resolution and lung repair, focusing on transcriptional and proteomic signatures and the effect of aging. Old mice incomplete, yet only delayed lung function recovery 8 weeks after Bleomycin instillation. This shift in structural and functional repair in old Bleomycin-treated mice was reflected in a temporal shift in gene and protein expression. We reveal gene signatures and signaling pathways which underpin the lung repair process. Importantly, the downregulation of WNT, BMP and TGFβ antagonists Frzb, Sfrp1, Dkk2, Grem1, Fst, Fstl1 and Inhba correlated with lung function improvement. Those genes constitute a network with functions in stem cell pathways, wound and pulmonary healing. We suggest that insufficient and delayed downregulation of those antagonists during fibrosis resolution in old mice explains the impaired regenerative outcome. Together, we identified signaling pathway molecules with relevance to lung regeneration that should be tested in depth experimentally as potential therapeutic targets for pulmonary fibrosis.