PDE4 inhibition in COPD

The inhibition of PDE4 as a novel approach in the treatment of COPD has been discussed and investigated by the medical community for many years. The PDE4 inhibitor roflumilast, is now indicated for maintenance treatment of severe COPD (FEV₁ post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment.^1-5 In this patient population, roflumilast 500µg once-daily reduces exacerbation rate and improves lung function.^3-5 

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.⁶

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.^7-9 As PDE4 is the major cAMP metabolizing enzyme, inhibition of PDE4 suppresses the inflammatory response.⁸ Also, by suppressing epidermal growth factor receptor-induced Mucin 5AC overexpression, PDE4 inhibition directly inhibits mucus production.¹⁰ Inhibition of PDE4 may also lead to minimization of airway remodelling by suppressing the release of TNFα.¹¹

 

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.⁸
• Modulate human airway epithelial cells that might support mucociliary clearance.¹⁰
• Tame human lung fibroblast to potentially mitigate a fibrotic response.¹²
• Inhibit proliferation of pulmonary artery smooth muscle cells and improve endothelial barrier integrity thereby reducing pulmonary vascular remodelling.¹¹

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.
• Modulate human airway epithelial cells that might support mucociliary clearance.
• Tame human lung fibroblast to potentially mitigate a fibrotic response.
• Inhibit proliferation of pulmonary artery smooth muscle cells and improve endothelial barrier integrity thereby reducing pulmonary vascular remodelling.

References

1.     Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of COPD. 2011. http://www.goldcopd.org

2.     Hatzelmann A, Morcillo E, Lungarella G, et al. The preclinical pharmacology of roflumilast – A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmcol Ther 2010:23;235-256.

3.     Calverly P, Rabe K, Goehring U-M, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685-694.

4.     Fabbri L, Calverly P, Izquierdo-Alonso J, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374:695-703.

5.     Rabe K. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Brit J Pharmacol 2011;163:53-67.

6.     Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 2001;108:671-680.

7.     Compton C, Gubb J, Nieman R, et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet 2001;358:265-270.

8.     Soto FJ & Hanania NA. Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease. Curr Opin Pulm Med 2005;11:129-134.

9.     Sturton G & Fitzgerald M. Phosphodiesterase 4 inhibitors for the treatment of COPD. Chest 2002;121:192S-196S.

10.   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.

11.   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.

12.   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.