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).