Epigenetic regulation of histone 3 acetylation and p53 by SIRT1 overexpression in an experimental model of alveolar epithelium damage.

Pulmonary fibrosis is a chronic, life-threatening respiratory disease characterized by high incidence and lack of effective treatments. This disease is associated with damage to the alveolar epithelium and heightened proapoptotic activity of p53, attributed to increased acetylation of its Lys381 residue. On the other hand, SIRT1 has been proposed as a therapeutic target for its ability to deacetylate key proteins such as histone 3 (H3), NF-ĸB, and p53, thus modulating cellular processes such as inflammation, apoptosis, differentiation, and oxidative stress, which could improve epithelial damage and fibrogenesis. Because SIRT1 can modulate key molecules related to lung fibrosis, this study examined the effect and localization of SIRT1 overexpression in A549 alveolar epithelial cells after bleomycin-induced injury. Two plasmids were used, one with SIRT1 cDNA and the other with a mutant H363Y catalytic site. SIRT1 expression and localization were analyzed by double immunofluorescence. SIRT1 phosphorylation at serine 47 as well as acetylation of p53 and H3 at lysine 381 and lysine 9, respectively, were also analyzed. Our results indicate that SIRT1 overexpression promotes H3 deacetylation, impacting epithelial-mesenchymal transition (EMT) and preventing pulmonary fibrosis. Additionally, our findings reveal that SIRT1 overexpression boosts its nuclear translocation and phosphorylation, deacetylates p53 and H3 after bleomycin damage, and preserves cell survival. The effect of SIRT1 on p53 and H3 deacetylation supports epigenetic control which may prevent cell death and EMT in pulmonary fibrosis.