Epigenetic Regulation in Idiopathic Pulmonary Fibrosis

Background: Idiopathic pulmonary fibrosis is a serious and fatal disease of unknown etiology. Currently, treatments for the condition are limited. In many diseases, epigenetics is a gleaming new avenue for development of new therapeutics. Newfound evidence suggests that epigenetics may play a critical role in IPF through modulation of superoxide dismutase 2 (SOD2), which is primarily localized in the mitochondria. In this study, we aim to elucidate the mechanism connecting epigenetics, SOD2, and IPF while also determining the relevance of a methyltransferase inhibitor, 5-AZA, in IPF.

Methods: Lungs from IPF patients were analyzed for SOD2 and methyltransferase expression by Western Blot. SOD2 was silenced using siRNA in human lung fibroblasts and then subsequently treated with TGFβ. In these cells, we measured the phenotypic consequences and differentiation of fibroblasts through changes in alpha smooth-muscle actin (αSMA). We also treated fibroblasts with methyltransferase inhibitor 5-AZA.

Results: In our study, we identified that IPF patients display increased expression of DNA methyltransferases and decreased expression of SOD2. Furthermore, our data suggests that SOD2 knockdown recapitulates the IPF phenotype in normal human lung fibroblasts. Interestingly, hypermethylation of SOD2 dampens the development of the IPF phenotype, which draws a potential connection between epigenetics and IPF progression.

Conclusion: Based on our data, it is evident that epigenetic regulation of SOD2 may be crucial for the progression and exacerbation of IPF. As a result of this, the inhibitor 5-AZA could possess a strong therapeutic potential based on the level of involvement of mythltransferase in SOD2 regulation.