PDE4 in COPD inflammation

Phosphodiesterases (PDEs) are a group of isozymes that metabolize the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). This makes them important regulators of intracellular signal transduction mediated by these molecules. PDE4 is the main cAMP-metabolizing isozyme in inflammatory and immune cells, pulmonary nerves and airway smooth muscle.1

 

Function of cyclic adenosine monophosphate (cAMP)

Cyclic AMP is a second messenger important in many biological processes. It is derived from adenosine triphosphate (ATP) and metabolized to 5’AMP (Figure 1). In the lung it is involved in the regulation of many functions related to inflammatory cells, mucociliary clearance, and fibrotic and pulmonary vascular remodeling. It suppresses immune and inflammatory cell activity (in inflammatory cells such as neutrophils, T-lymphocytes and macrophages), relaxes airway smooth muscle and modulates pulmonary nerve activity.1

Figure 1: Synthesis and degradation of cAMP in the cell.

 

An increase in the intracellular concentration of cAMP interferes with the expression of pro-inflammatory mediators such as TNF-α and inhibits the activity of inflammatory cells.

 

Effect of PDE4

The degradation of cAMP to 5’AMP is catalyzed by PDE4; cAMP-specific PDE4 is expressed in inflammatory and several other airway cell types involved in the pathogenesis of COPD.1

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Figure 2: Effect of PDE4 on inflammatory cells


PDE4 degrades cAMP into inactive 5’AMP. When intracellular levels of cAMP fall, inflammatory cells become activated (Figure 2).



Role of inflammation in COPD

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Reference

  1. Soto FJ & Hanania NA. Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease. Curr Opin Pulm Med 2005;11:129-34.

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PDE4 inhibition in COPD

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