Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide, affecting around 25-30% of all cigarette smokers, with disease numbers likely to increase due to the increased use of tobacco products. COPD is characterised by chronic inflammation, which leads to the progressive destruction of alveolar tissue, airway remodelling and mucus hypersecretion, resulting in a progressive decline in lung function and increased breathlessness. High doses of steroids are widely used to suppress symptoms (ineffectively), but there are no treatments that halt the progression of disease.
Epigenetic changes through aberrant acetylation of cellular factors have been implicated in COPD pathogenesis. Histone acetyltransferases (HATs) acetylate lysine residues on histones and non-histone proteins and are associated with gene activation and inflammation. They are counteracted by histone deacetylases (HDACs), which are associated with gene repression. An aberrant balance between HAT and HDAC activity can therefore have dramatic biological consequences. For example, decreases in HDAC2 activity has been associated with reduced steroid responsiveness. Few studies have thoroughly investigated the roles of HDACs and HATs or their targets in COPD pathogenesis. The elucidation of their roles and their therapeutic modulation may identify effective ways to treat COPD.
Our lack of understanding of COPD pathogenesis and consequently the development of therapies has been severely hampered by the lack of an appropriate animal model that recapitulates aspects of human disease in a reasonable time frame. We have generated a novel mouse model of COPD that displays airway inflammation, mucus hypersecretion, emphysema-like tissue destruction, and altered lung function in just 8 weeks.
In pioneering studies we demonstrate that in experimental COPD, HATs are selectively increased, with a corresponding decrease in some HDACs, mimicking human disease. These specific changes in enzymes involved in acetylation may reflect potential targets to treat COPD or improve the effectiveness of symptom treatments.