Coactivator-Associated Arginine Methyltransferase-1 Function in Alveolar Epithelial Senescence and Elastase-Induced Emphysema Susceptibility

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible loss of lung function and is one of the most prevalent and severe diseases worldwide. A major feature of COPD is emphysema, which is the progressive loss of alveolar tissue. Coactivator-associated arginine methyltransferase-1 (CARM1) regulates histone methylation and the transcription of genes involved in senescence, proliferation, and differentiation. Complete loss of CARM1 leads to disrupted differentiation and maturation of alveolar epithelial type II (ATII) cells. We thus hypothesized that CARM1 regulates the development and progression of emphysema. To address this, we investigated the contribution of CARM1 to alveolar rarefication using the mouse model of elastase-induced emphysema in vivo and small interfering (si)RNA-mediated knockdown in ATII-like LA4 cells in vitro. We demonstrate that emphysema progression in vivo is associated with a time-dependent down-regulation of CARM1. Importantly, elastase-treated CARM1 haploinsufficient mice show significantly increased airspace enlargement (52.5 ± 9.6 μm versus 38.8 ± 5.5 μm; P < 0.01) and lung compliance (2.8 ± 0.32 μl/cm H2O versus 2.4 ± 0.4 μl/cm H2O; P < 0.04) compared with controls. The knockdown of CARM1 in LA4 cells led to decreased sirtuin 1 expression (0.034 ± 0.003 versus 0.022 ± 0.001; P < 0.05) but increased expression of p16 (0.27 ± 0.013 versus 0.31 ± 0.010; P < 0.5) and p21 (0.81 ± 0.088 versus 1.28 ± 0.063; P < 0.01) and higher β-galactosidase-positive senescent cells (50.57 ± 7.36% versus 2.21 ± 0.34%; P < 0.001) compared with scrambled siRNA. We further demonstrated that CARM1 haploinsufficiency impairs transdifferentiation and wound healing (32.18 ± 0.9512% versus 8.769 ± 1.967%; P < 0.001) of alveolar epithelial cells. Overall, these results reveal a novel function of CARM1 in regulating emphysema development and premature lung aging via alveolar senescence as well as impaired regeneration, repair, and differentiation of ATII cells.

Metabolomics screening identifies reducedL-carnitine to be associated with progressive emphysema

“…Despite PPE being shown to be cleared from the lungs of rodents within 24 h [37], airspace enlargement continues long after this time [18,36]; indeed we have recently shown emphysema following a single oropharangeal application of PPE to continue progressing to day 161 [19]. Figure 1(A) clearly demonstrates a time-dependent enlargement of the airspaces in H&E-stained lung sections from PPE-treated mice compared with control animals.…”

“…This may not be the ideal tissue for a biomarker given the difficulties in obtaining biopsies from patients, but it is critical in furthering our understanding of the mechanisms of disease progression. To that end we chose to assess the well-established PPE-induced murine model of emphysema, as it induces airspace enlargement similar to that observed in COPD patients [36], a single treatment leads to progressive disease that is associated with senescence of alveolar epithelial cells [19] and accompanied by increased levels of apoptosis [47]. In the present study, we confirm that a single oropharyngeal application of PPE resulted in a progressive emphysematous phenotype to day 161, which is associated with a steady decline in lung function and an increase in lung volume that accompanies an increase in airspace enlargement.…”

“…In the present study, for the first time, we use targeted metabolomics to assess changes in the metabolome locally to the lung and systemically in serum during disease progression, using the well-established porcine pancreatic elastase (PPE)-induced model of murine emphysema [18,19]. We demonstrated that the progression of emphysema is associated with reduced levels of Lcarnitine in the lung.…”

Cholesterol metabolism promotes B‐cell positioning during immune pathogenesis of chronic obstructive pulmonary disease

“…In combination, this suggests that impaired cytokine secretion by professional APCs is not a contributing factor in CH25H‐deficient mice. Furthermore, recent evidence revealed that depletion of alveolar macrophages ameliorated elastase‐induced emphysema (Ueno et al , ), an iBALT‐independent emphysema mouse model (Dau et al , ; Sarker et al , ). Therefore, we utilized this model to demonstrate that loss of CH25H in macrophages did not impact upon emphysema development.…”

Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema

“…Lung function analysis were performed as previously reported 36 . Briefly, lung function was assessed by a forced maneuver system and a Fine-Pointe RC system (Buxco Research Systems; Wilmington, NC, USA).…”