Accelerating lung epithelial cell senescence in reduced CARM1 mice enhances elastase-induced emphysema

Emphysema, a key feature of chronic obstructive pulmonary disease is characterized by progressive destruction of pulmonary alveoli. Emphysema development involves alveolar senescence. CARM1, an arginine methyltransferase and transcriptional cofactor, methylating histone and non-histone proteins found crucial for regulating senescence (Wang, BMC Mol Biol 2013). We therefore, hypothesized that loss of CARM1 induces alveolar epithelial cell senescence and thus enhances the susceptibility to elastase-induced emphysema. Porcine pancreatic elastase (PPE) treated C57BL/6 (WT) or CARM1+/- mice were analyzed for lung function, histology, and gene expression on day 28, 56, or 161. Alveolar epithelial type II-like murine LA-4 cells treated with CARM1-specific siRNA were analyzed for senescence by mRNA/protein expression and for functional wound healing assays. PPE-treated WT mice showed significant progressive decline in lung function measured by Tiffeneau index, compliance and airspace enlargement quantified by mean chord length. CARM1 mRNA was downregulated during emphysema progression. PPE-treated CARM1+/- mice showed significant airspace enlargement (52,5 ± 9,6 µm versus 38,8 ± 5,5 µm, respectively SD p The results indicate that CARM1 is an important modulator of type II alveolar epithelial cell by regulating senescence and reduction of functional CARM1 is an underlying mechanism of susceptibility to emphysema.