Premature aging in Zmpste24 deficient mice protects them from bleomycin induced lung fibrosis through upregulation of antifibrotic microRNAs

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease of unknown etiology, elusive pathogenesis an limited therapeutic options. The mechanisms linking IPF to aging are uncertain, but several aging-associated abnormalities, such as shortening of telomeres and mitochondrial dysfunction occur exaggeratedly in this disease. Since models of lung fibrosis using aged mice are difficult to perform, it has been suggested that genetically modified mice that display acceletaded aging may be useful to understand some aging-associated mechanisms that may contribute to the development of lung fibrosis. We evaluated the fibrotic response to bleomycin in wildtype (WT) and Zmpste24 deficient old mice and the transcriptional signature using Murine Genome U74v2 Set. ZMPSTE24 process the nuclear lamin A and its absence provokes accelerated aging. Surprinsingly, we found that aged Zmpste24 deficient mice showed less lung inflammation and fibrosis at 3 weeks after bleomycin injury compared with aged WT counterparts. The attenuation of the fibrotic response was confirmed by a significant decrease in lung hydroxyproline content. Global gene expression analysis revealed an increased expression of several antifibrotic microRNAs including miR23a, miR27a, miR29a and miR29b-1 in bleomycin-damaged lungs of Zmpste24 KO mice, which was validated by qPCR. As expected, several targets of these microRNAs, including collagens were decreased. Our results suggest that absence of Zmpste24 protects aged mice from the development of bleomycin-induced lung fibrosis by the upregulation of microRNAs with antifibrotic activity. Funding: CONACyT 281074