Phosphodiesterase isoforms and cAMP compartments in the development of new therapies for obstructive pulmonary diseases

Abstract

The second messenger molecule 3'5'-cyclic adenosine monophosphate (cAMP) imparts several beneficial effects in lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). While cAMP is bronchodilatory in asthma and COPD, it also displays anti-fibrotic properties that limit fibrosis. Phosphodiesterases (PDEs) metabolize cAMP and thus regulate cAMP signaling. While some existing therapies inhibit PDEs, there are only broad family specific inhibitors. The understanding of cAMP signaling compartments, some centered around lipid rafts/caveolae, has led to interest in defining how specific PDE isoforms maintain these signaling microdomains. The possible altered expression of PDEs, and thus abnormal cAMP signaling, in obstructive lung diseases has been poorly explored. We propose that inhibition of specific PDE isoforms can improve therapy of obstructive lung diseases by amplifying specific cAMP signals in discreet microdomains.

Figure 1

PDE inhibition in obstructive lung diseases. Pulmonary diseases such as COPD, asthma and IPF are characterized a certain degree of airway obstruction, chronic inflammation and airway remodeling. Global PDE inhibition increases cyclic nucleotide signaling and therefore provides therapeutic benefit. However, the widespread expression of PDEs in all types of lung cells causes broad inhibition of a family of isoforms and eventually also leads to unwanted side effects. Specific inhibitors of single PDE isoforms, particularly those acting specifically in particular subcellular signaling microdomains, have the potential to be more effective and specific. See text for further detail.

Figure 2

PDEs facilitate formation and maintenance of cAMP signaling compartments. Individual PDE isoforms are expressed in discrete subcellular locations where they regulate cyclic nucleotide signaling in specific signaling compartments. Some of these specific findings are illustrated here. Understanding the microdomains where these PDEs are expressed and the cellular functions they regulate can lead to more specific therapeutic approaches. See text for further detail.