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.