Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases

Abstract

Phosphodiesterases (PDEs) The selective targeting of phosphodiesterases type 4 (PDE4) has been actively pursued as a novel therapeutic approach in the treatment of respiratory diseases associated with inflammatory processes such as asthma and chronic obstructive pulmonary disease (COPD). The rationale for their use in respiratory disease is based on the clinical efficacy of non-selective PDE inhibitors such as theophylline, the detection of PDE4 in many of the cells involved in these diseases and the emergence of positive results from a number of pharmacological studies and clinical trials currently evaluating the efficacy of selective PDE4 inhibitors in respiratory diseases (Barnette 1999, Spina 2000. PDE4 represent the major class of PDE expressed in human inflammatory cells (Wang et al. 1999) and in particular in macrophages, eosinophils and neutrophils, the main cell types present in the lungs of asthmatic and COPD patients.PDE4 are members of the phosphodiesterase (PDE) superfamily of enzymes, which comprises at least 11 members hydrolyzing cyclic AMP (adenosine 3',5'-cyclic monophosphate) and/or cyclic GMP (guanosine 3',5'-cyclic monophosphate) (Houslay et al. 1998, Conti & Jin 1999, Giembycz 2000. In the case of PDE4, there are four gene products and multiple splice variants resulting in a variety of PDE4 isoforms. PDE4 selectively catalyse the hydrolysis of cAMP and the anti-inflammatory effects of selective PDE4 inhibitors were supposed to result of the reduction of cAMP hydrolysis. However, some recent studies have demonstrated that PDE4 could also act through cAMP-independent mechanisms. Indeed, we have observed that PDE4 inhibitors triggered a cAMP-independent inhibition of fMLP-induced O 2. -release from bronchoalveolar lavage cells of rats exposed to lipopolysaccharide . We also showed that the inhibitory effect of PDE4 inhibitors on O 2. -production is mediated by the activation of p44/42 MAPK and that PDE4 inhibit p44/42 MAPK by a direct interaction ). This study allowed us to identify a novel mechanism involving MAPK in the pathway connecting PDE4 to fMLP-induced O 2. -generation in neutrophils.

Involvement of MMP-12 and phosphodiesterase type 4 in cigarette smoke-induced inflammation in mice

“…Glucocorticoids, as well as PDE4 inhibitors, have been reported to be potent anti-inflammatory compounds in vitro and in vivo in various animal models [30]. To establish the importance of the smoking model in predicting efficacy in human disease, the current authors tested representatives from these two drug classes, dexamethasone and cilomilast, in the experimental model and compared it with the LPS model.…”

Phosphodiesterase Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

“…In other chronic cigarette smoke exposure studies, roflumilast N-oxide (oral treatment for 7 months) fully prevented emphysema in mice [64], and the PDE4 inhibitor GPD-1116 (oral treatment for 8 weeks) also markedly attenuated the development of cigarette smoke-induced emphysema in the senescence-accelerated mouse P1 strain [65]. PDE4 inhibitors have also been shown to reduce MMP9 and TGF-β release during LPS-induced lung injury in mice [66]. …”

“…Local administration of PDE4 and dual PDE3/4 inhibitors directly to the lung also inhibits LPS-induced neutrophil recruitment to the lung in a range of species including rats [66,67,68], ferrets [66] and pigs [66]. In addition, local administration of an inhaled PDE3/4 inhibitor SDZ ISQ 844 in dogs decreased airways responsiveness to inhaled methacholine at a dose which did not affect baseline respiratory resistance [69].…”

“…A number of highly potent inhaled PDE4 inhibitors have thus been developed, including RP 73401 [26], AWD 12-281 [66], GSK 256066 [85] and, more recently, a novel class of PDE4 inhibitors [92]. Unfortunately, a number of clinical trials have not shown these to have any major therapeutic effect, either in patients with asthma or COPD [66,85]. It is not known why these drugs have failed clinically when administered by inhalation but have been effective when administered orally [93].…”

Screening for phosphodiesterase inhibitory activity of Thai medicinal plants

“…Recently, some PDE inhibitors have been approved for medical uses by US-FDA. For example, a PDE-4 inhibitor, cilomilast, can be used for the treatment of chronic obstructive pulmonary disease (COPD) (Lagente et al, 2005). A PDE-5 inhibitor, Sildenafil, is approved for the erectile dysfunction treatment (Moreland et al, 1999;Brock, 2002).…”