Discussion
The murine model of CS-induced pulmonary emphysema has many similarities
to human COPD, including growth delay
(Chen, Hansen, Jones, Vlahos, Anderson &
Morris, 2008; He, Li, Sun, Zeng, Lu &
Xie, 2018), hyper-inflammatory responses and enhanced oxidative stress
(Kameyama et al., 2018;
Sasaki et al., 2015). By using the
C57BL/6 mice strain in this study, we enhanced the susceptibility to CS
exposure (Yao et al., 2008). TNF-α and
IL-8 were chosen as the representative inflammatory biomarkers because
both play key roles in the pathogenesis of CS-induced pulmonary
inflammation (de Carvalho et al., 2016;
Fujita et al., 2016).
The PDEs are classified into 11 super-families
(Kawamatawong, 2017). Involvement of PDE
isoforms such as PDE3, PDE4, PDE5 and PDE7 has been demonstrated in the
pathogenesis of airway inflammation and hyper-responsiveness
(Beute et al., 2018;
Dunne et al., 2019;
Zuo, Cattani-Cavalieri, Musheshe, Nikolaev
& Schmidt, 2019). Similar to previous studies
(Marwick et al., 2009;
Sun, Li, Gong, Ren, Wan & Deng, 2012),
the expression of ROS, IL-8 and TNF-α in mice exposed to long-term CS,
was elevated, and was associated with a reduction in HDAC-2 activity and
emphysema-like pulmonary damage. As with human COPD, in which no
treatment modalities are able to repair pulmonary emphysematous
destruction, PTX or ROF therapy in the present study did not mitigate
the CS-induced pulmonary emphysema (no reduction in Lm). However, the
PDEIs therapy demonstrated some anti-inflammatory merits: IL-8
expression was down-regulated by PTX and THEO, TNF-α was preferentially
decreased by PTX and HDAC-2 activity was partially restored when using
either of these PDEIs. This restoration was preferentially associated
with the downregulation of ROS, rather than a reduction in any single
cytokine.
PTX is the strongest anti-inflammatory agent among the three PDEIs if
the inhibitory effects on IL-8, TNF-α and ROS are considered. PTX has
never been recommended for COPD treatment, as early clinical trials with
PTX monotherapy showed no significant clinical benefits when considering
oxygenation and amelioration of pulmonary function in patients with COPD
(Fallahi, Ghayumi & Moarref, 2013;
Sasse, Causing, Stansbury & Light,
1995). Unfortunately, thus far, there is no agent that can reverse the
damage done when impaired lung function is evident, or decrease the
decline in the pulmonary function of patients with COPD. Variables such
as the reduction rate of exacerbation and improving the quality of life
of patients, have become the major study endpoints in most COPD clinical
studies.
Recent research revealed that the benefit of ROF treatment in COPD is
related to the inhibition of eosinophils rather than neutrophils
(Rabe et al., 2018), despite the
pathogenesis of COPD being more closely related to CD8 skewness and
neutrophil infiltration (Eapen, Myers,
Walters & Sohal, 2017). This could suggest that the subjects enrolled
in studies concern with the clinical efficacy of ROF, might include some
patients with overlapping asthma. Clinical trials based on patients with
COPD using a combination of low-dose oral THEO and inhaled
corticosteroids did not show significant benefits
(Cosio et al., 2016;
Devereux et al., 2018). PTX possesses
preferential inhibitory effects on CD8 and neutrophils
(Costantini et al., 2010;
Konrad, Neudeck, Vollmer, Ngamsri, Thiel
& Reutershan, 2013), and when combined with a GC, as shown in our
current study, its effect on ROS inhibition is stronger than that of
THEO and ROF. Therefore, the efficacy of PTX in COPD treatment should be
re-evaluated using adequate clinical variables, such as the rate of lung
function decline and the frequency of acute exacerbations.
When considered together, we concluded that the reduction of HDAC-2
activity is associated with the up-regulation of ROS. THEO, as well as
PTX and ROF, can restore HDAC-2 activity by alleviating oxidative
stress.