PDE4 inhibition in COPD

The inhibition of PDE4 as a new approach in the treatment of COPD has been discussed and investigated by the medical community for many years. The crucial role of PDE4 in COPD-specific inflammation makes it a very interesting target.

Effect of PDE4 inhibition on cyclic AMP levels

Inhibition of PDE4 can increase the intracellular concentration of cAMP by inhibiting its degradation leading to reduced inflammatory cell activity.¹

Figure 1: Effect of PDE4 inhibition on inflammatory cell activity.

PDE4 inhibition leads to an accumulation of intracellular cAMP. As intracellular cAMP levels rise it activates enzymes reducing inflammatory cell activity.

Physiological effects of PDE4 inhibition in the lung

A large body of pre-clinical research has shown that PDE4 inhibition has the potential to target the three main components of COPD: bronchoconstriction, mucus hypersecretion and airway remodelling.^2-4 As PDE4 is the major cAMP metabolising enzyme, inhibition of PDE4 suppresses the inflammatory response.³ Also, by suppressing epidermal growth factor receptor-induced Mucin 5AC overexpression, PDE4 inhibition directly inhibits mucus production.⁵ Inhibition of PDE4 may also lead to minimisation of airway remodelling by suppressing the release of TNFα.⁶

Proposed beneficial actions of PDE4 inhibition in COPD

Figure 2: Inhibition of PDE4.

In Summary:

PDE4 inhibition interferes with the breakdown of cAMP, leading to the accumulation of intracellular cAMP. In turn, an elevated concentration of intracellular cAMP activates protein kinase A, which enhances phosphorylation of proteins. This chain of biochemical reactions and physiological processes should:

• Inhibit numerous inflammatory cell functions, e.g. proliferation, release of cytokines and chemokines, reactive oxygen species, arachidonic acid metabolites, chemotaxis and proteases.³
•  Modulate human airway epithelial cells that might support mucociliary clearance.⁵
• Tame human lung fibroblast to potentially mitigate a fibrotic response.⁷
• Inhibit proliferation of pulmonary artery smooth muscle cells and improve endothelial barrier integrity thereby reducing pulmonary vascular remodelling.⁶

References

1. Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 2001;108:671-680.
2. Torphy TJ, Barnette MS, Underwood DC, et al. Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm Pharmacol Ther 1999;12:131-135.
3. Soto FJ & Hanania NA. Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease. Curr Opin Pulm Med 2005;11:129-134.
4. Sturton G & Fitzgerald M. Phosphodiesterase 4 inhibitors for the treatment of COPD. Chest 2002;121:192S-196S.
5. Mata M, Sarria B, Buenestado A, et al. Phosphodiesterase 4 inhibition decreases MUC5AC expression induced by epidermal growth factor in human airway epithelial cells. Thorax 2005;60:144-152.
6. Profita M, Chiappara G, Mirabella F, et al. Effect of cilomilast (Ariflo) on TNF-alpha, IL-8, and GM-CSF release by airway cells of patients with COPD. Thorax 2003;58:573-579.
7. Selige J, Tenor H, Hatzelmann A, et al. Cytokine-dependent balance of mitogenic effects in primary human lung fibroblasts related to cyclic AMP signaling and phosphodiesterase 4 inhibition. J Cell Physiol 2010;223:317-326.