Dissecting the role of microRNAs and cellular aging in the pathophysiology of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is an interstitial lung disease, characterized by a progressive lung fibrosis, that leads to chronic respiratory failure, and death within 5 year from diagnosis. The impaired lung repair following injury is strongly associated with aging. To elucidate aging processes and miRNAs involved in the IPF's pathogenesis, we performed a cell-based functional screening for inducers of senescence on 2000 miRNA mimics tested on primary murine ATIIs. The primary screening identified 18 miRNAs that were followed up for their ability in inhibiting ATII to ATI transdifferentiation. Only 2 miRNAs were selected for this combined effect. Of note both these miRNAs are HypoxiamiR, a large family of miRNAs known to be upregulated upon hypoxic conditions. The importance of selected miRNAs is known in the development of fibrotic lung scarring and remodelling, but their role was only described in fibroblast, and nothing was known on their role in ATII cellular senescence and transdifferentiation. Our results show that the endogenous expression of selected miRNAs increase, together with HIF-1-alpha, during bleomycin induced lung damaged in mice. We also confirmed that these miRNAs are expressed by both alveolar fibroblasts and ATII cells, and their expression is increased upon bleomycin damage in both cell types. Accordingly, both miRNAs scored upregulated in IPF primary human ATIIs, thus confirming their role in the human disease. Given the possibility to reduce miRNA levels in vivo using anti-sense oligonucleotides (ASOs), we will assess the efficacy of anti-miRNA-ASOs in reducing lung fibrotic scarring upon bleomycin administration in both young and aged mice.