Targeting PDE3 Abrogates the Hallmarks of Asthma in Asthma Models

Objective: Case reports related to status asthmaticus showed that enoximone, which is a smooth muscle relaxant that inhibits PDE3, is beneficial and lifesaving. Off label use of enoximone has steroid sparing properties. From PDE3 inhibition it is not known that it has anti-inflammatory effects. Here, we investigated the pathophysiological role and disease modifying effects of PDE3 in acute and chronic house dust mite (HDM)-driven asthma mouse models. Methods: Bronchial hyperreactivity (BHR) and allergic airway inflammation (AAI) and airway remodelling was investigated by Buxco, histology and flowcytometry in chronic HDM-driven asthma models. The pathophysiological role was studied by intervention of PDE3 by transgenic mice lacking PDE3 or wild type mice treated with the PDE3 inhibitor enoximone when AAI was already established. Mucosal barrier function was investigated by measuring albumin leakage and the presence of albumin in lung tissue. Results: Mice lacking PDE3 or treated with the PDE3 inhibitor enoximone showed reduced BHR; reduced AAI as measured by BAL eosinophilia and Th2-cell cytokine profile and showed improved mucosal barrier function when compared to wild type control mice in the HDM-driven asthma models. Having established HDM driven AAI, reduced BHR, reduced smooth muscle mass and reduced mucus hypersecretion depict the role of enoximone in abrogating airway remodelling. In addition, diminished inflammatory cells and epithelial mast cells depicted its broader anti-inflammatory effects of PDE3 inhibition when intervention with enoximone or placebo starts after already established HDM driven AAI. Conclusion: Taken together this study prove the pathophysiological role of PDE3 in asthma models