Emphysema susceptibility is modulated by the epigenetic regulator HMGN5
Einleitung: Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis, small airway remodeling and emphysema. Emphysema is the destruction of alveolar structures, leading to enlarged air spaces and reduced surface area impairing the ability for gaseous exchange. Smoking remains the main environmental risk factor for COPD, however, genetic factors also have a great impact on COPD susceptibility. We previously detected spontaneous emphysema development in HMGN5 deficient mice. HMGN5 binds to the nucleosomal core particle of chromatin, competing with histone H1, thus altering chromatin structure and function. Here we investigate the role of HMGN5 during the development of emphysema using the established murine porcine pancreatic elastase (PPE) model.
Methoden: Wild type (WT) C57BL/6 and HMGN5 deficient mice were exposed to a single oropharyngeal application of PPE (40U/kg) and analyzed 28 days later for lung function, gene expression and histologically. Additionally, alveolar epithelial type II-like murine LA-4 cells were transfected with HMGN5-specific siRNA and assessed for levels of proliferation, apoptosis and in functional wound healing assays.
Ergebnisse: In vitro studies revealed that downregulation of HMGN5 with siRNA impaired the wound healing ability of LA4 cells and increased the number of apoptotic LA4 cells with a concomitant decrease in their proliferation rate. In vivo, WT mice exposed to PPE demonstrated reduced expression of HMGN5 after 28 days. Furthermore, HMGN5 deficient mice had greater impaired lung function compared to WT controls following PPE exposure (lung compliance of 0.084 ± 0.007 ml/cmH2O vs. 0.070 ± 0.006 ml/cmH2O respectively, p < 0.001), with greater evidence of emphysema development upon histological analysis.
Diskussion: Taken together, this data suggests a novel causal link between epigenetic regulation and emphysema development via increased apoptosis and impaired cell proliferation, highlighting potential new therapeutic avenues for impeding emphysema progression.