PDE4 inhibitors and oxidative stress

PDE4 belongs to the PDE1-11 superfamily, specifically degrades cAMP and is present in almost all cells with the exception of platelets. Selective inhibition of PDE4 augments cellular cAMP content that improves chronic inflammation or tissue remodeling. Consequently, over almost three decades industry endeavored to develop PDE4 inhibitors. Roflumilast has now been approved in EU/US as the first PDE4 inhibitor for treatment in severe chronic obstructive pulmonary disease (COPD). In COPD an enhanced burden of oxidative stress is likely promoting key disease mechanisms such as COPD-related inflammation, lung remodeling or mucociliary malfunction. Neutrophils, which are considered as primary effectors cells in COPD almost exclusively express PDE4. That PDE4 inhibitors such as rolipram or Ro20-1724 suppress fMLP-induced superoxide radical release from neutrophils was described in 1990. These findings were probably the first demonstration that PDE4 inhibitors may mitigate oxidative stress. Such initial observations in neutrophils were now extended to numerous other cells involved in COPD, specifically structural cells. Indeed, PDE4 inhibitors reduce ROS formation in airway epithelial cells, lung fibroblasts, endothelial cells or pulmonary artery smooth muscle cells. Mechanistically, PDE4 inhibitors may act by (i) reducing NADPH oxidase (NOX) activity secondary to inactivating Rac, (ii) attenuating the expression levels of some NOX isoforms. Cellular ROS levels may result from the balance between ROS formation mainly attributed to the NOX system and ROS quenching secondary to the Nrf2-dependent anti-oxidative machinery. Aside from its potential to reduce ROS formation more recently an increase in cAMP was related to enhanced Nrf2 nuclear accumulation, which may support the anti-oxidative machinery. Evidence for this concept was first generated in dermal fibroblasts. Preliminary data from human umbilical vein endothelial cells showed that inhibition of PDE4 (1µM roflumilast N-oxide) when PDE3 was blocked (10µM motapizone) resulted in an about 1.9-fold increase in nuclear Nrf2 following a 3 hours incubation time (roflumilast N-oxide or motapizone on their own were ineffective). Thus, the notion may be raised that PDE4 inhibitors potentially attack excessive ROS twofold, by inhibiting generation and accelerating degradation. More studies are required to further support such a concept. Lung fibrotic remodeling has been related to oxidative stress and indeed N-acetyl cysteine (NAC) may have some clinical benefit in idiopathic pulmonary fibrosis. In vivo, NAC partly suppresses the bleomycin-induced lung fibrotic response indicating a critical role of ROS to mediate fibrosis. The PDE4 inhibitor roflumilast was shown to mitigate lung fibrosis following bleomycin in preventive but also therapeutic protocols in mice and rats that was paralleled by a partial reduction of lipid hydroperoxides (markers of oxidative stress) in BAL. Taken together, there is firm evidence that PDE4 inhibitors suppress oxidative stress in vitro that is also reflected in vivo. One may postulate that reducing the burden of oxidative stress may be one of the mechanisms translating into the therapeutic success of roflumilast in severe COPD although this notion remains to be specifically addressed in clinical investigations.