5.1 Phosphodiesterase enzymes (PDEs)
Phosphodiesterase enzymes (PDEs) are a large superfamily of enzymes that
catalyze the hydrolysis of secondary messengers such as cAMP and cyclic
guanosine mono-phosphate (cGMP) into their inactive 5′ monophosphate;
thus regulating their intracellular level as well as the amplitude and
duration of their signaling (Hertz et al., 2009).
Based on amino acid
sequences, tissue distribution and pharmacological properties, PDEs
could be classified into 11 families, namely
PDE1-PDE11. Similarly, PDEs
can be also grouped into three categories according to their substrate
specificities including, cAMP-selective
hydrolases (PDE4, 7 and 8),
cGMP-selective hydrolases (PDE5, 6, and 9) and hydrolases for both cAMP
and cGMP (PDE1, 2, 3, 10, and 11) (Azevedo et al., 2014).
Regarding PDE4, it was accounted
to represent the predominant isoenzyme responsible for regulating cAMP
levels in many cell types within the lung including airway epithelial
cells, airway smooth muscle cells and pulmonary vascular endothelium.
PDE4 was also noticed to be widely distributed in various inflammatory
cells, like neutrophils, T lymphocytes, eosinophils, monocytes and
basophils (van Schalkwyk et al., 2005; Halpin, 2008).
Notably, cAMP has a direct
significant role in different inflammatory pathways via inhibiting ROS
generation and pro-inflammatory cytokines production, mainly TNF-α and
IL-6; (Shames et al., 2001; Isoni et al., 2009). cAMP could also promote
the production of anti-inflammatory mediators such as IL-10 which was
identified as a “cytokine synthesis inhibitory factor”, and acted as a
principle regulator in the
JAK-STAT
signaling pathway (Redford et al., 2011). Therefore, elevating cAMP
level within the pulmonary tissue, vascular and inflammatory cells can
provide an efficient anti-inflammatory action (Li et al., 2018).
On the other hand, it was found that the capacity of PDEs for cAMP
hydrolysis is greater than the maximum rate of its synthesis. Therefore,
minute reduction in PDEs activity can result in high elevation in cAMP
level with significant changes in the activity of its dependent protein
kinase (Halpin, 2008). The notice that pushed scientists since 1970 to
investigate the potential therapeutic importance of inhibiting PDE4
activity (Weiss and Hait, 1977).