Abbreviations
COPD, chronic obstructive pulmonary disease;
HDAC-2, histone deacetylase-2;
CS, cigarette smoke;
Lm, mean linear intercept;
ROS, reactive oxygen species;
BALF, bronchoalveolar lavage fluid;
ROF, roflumilast;
PTX, pentoxifylline;
THEO, theophylline;
TRI, Triamcinolone acetonide.
Introduction
Chronic obstructive pulmonary disease (COPD) affects approximately 13% of people over the age of 40 (Fang et al., 2018) and was the fifth leading cause of death in China in the year of 2016 (Collaborators, 2017). Unlike bronchial asthma, in which the majority of the patients’ symptoms can be well controlled using glucocorticoids (GCs), the response to GC treatment in patients with COPD is not as effective as the response seen in asthmatic patients. This insensitivity to GCs is associated with a reduction in histone deacetylase-2 (HDAC2) activity, and in line with COPD clinical severity (Barnes, Ito & Adcock, 2004; Footitt et al., 2016; Ito et al., 2005). Excessive inflammation, together with enhanced oxidative stress is an important mechanism for this decrease in HDAC-2 activity in patients with COPD (Barnes, 2016; Footitt et al., 2016). Restoration of GC sensitivity is postulated as a novel approach for COPD management (Marwick, Adcock & Chung, 2010; Mitani, Ito, Vuppusetty, Barnes & Mercado, 2016).
Theophylline (THEO), pentoxifylline (PTX) and roflumilast (ROF) are three commonly prescribed phosphodiesterase (PDE) inhibitors for anti-inflammatory treatment. THEO is prescribed as a bronchodilator while PTX is indicated for occlusive extremity artery disease (intermittent claudication)(Chopra, Chopra, Aggarwal & Parashar, 1988). ROF is a relatively new agent that selectively inhibits PDE-4 on inflammatory cells (Kawamatawong, 2017; Sakkas, Mavropoulos & Bogdanos, 2017), and is indicated in adults with severe COPD.
Certain laboratory studies have claimed that GC sensitivity could be re-established by using THEO to up-regulate HDAC-2 expression (Ranjani & Vinotha, 2017; To et al., 2010), however adding THEO to inhaled GCs did not result in improved clinical outcomes (Devereux et al., 2018). We consider whether other anti-inflammatory PDE inhibitors (PDEIs), such as PTX and ROF, had a similar or even greater effect on restoring GC-sensitivity by restoring HDAC-2 activity, thereby providing a novel avenue for clinical investigation.